Carbamoylpyrolidone derivatives and drugs for senile dementia

ABSTRACT

A compound of the formula: ##STR1## (wherein R is phenoxy optionally substituted by a halogen, methoxy, or methyl group, ##STR2## one of A and B is ##STR3## and the other is &gt;CH 2  : R 1  is hydrogen or C 1  -C 5  alkyl; Z 1  is phenyl, benzyl, or isoxazolyl each optionally substituted by a halogen, methoxy, or methyl group; Z 2  is hydrogen, C 1  -C 5  alkyl, C 2  -C 5  alkenyl, or phenyl optionally mono-, di-, or tri-substituted by a halogen, methoxy, or methyl group; or Z 1  and Z 2  taken together with the adjacent nitrogen atom may form 5-membered heterocyclic group; Z 3  is C 1  -C 5  hydroxyalkyl, di(C 1  -C 5  alkyl)sulfamoyl, 6-membered heterocyclic group, phenyl, benzyl, or phenylsulfonyl each phenyl moiety of the last three members being optionally substituted by a halogen, methoxy, or methyl group; Z 4  is phenyl optionally substituted by a halogen, methoxy, or methyl group or 5- or 6-membered heterocyclic group which is optionally substituted by a halogen, methoxy, or methyl group and which can be optionally condensed with a benzene ring; Z 5  is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; Z 6  is thienyl or phenyl each optionally substituted by a halogen, methoxy, or methyl group; m is an integer from 0 to 2; n is an integer from 2 to 3) or its pharmaceutical acceptable acid addition salt being useful as a drug for senile dementia, psychotropic, or antiamnesia agent is provided through several routes.

BACKGROUND OF THE INVENTION

This invention relates to carbamoylpyrrolidone derivatives. Moreparticularly, this invention is directed to carbamoylpyrrolidonederivatives which have been found to be particularly available as a drugfor senile dementia, psychotropic, and/or antiamnesia agents, to theirpreparation, to their use and to pharmaceutical formulations containingthe compounds.

Pyrrolidone derivatives have heretofore been known as drugs for braininsufficiency disease and so on, for example, in EP Pat. Publn. No.89900-B, in U.S. Pat. Publn. No. 4,369,139, and in U.S. Pat. Publn. No.4,118,396.

The inventors of the present invention have been studying antiamnesiaagents of the pyrrolidone family including such compounds. Thus, thepresent invention has been established, where the compounds of thepresent invention can be applicable for treating some kinds of seniledementia.

SUMMARY OF THE INVENTION

According to the present invention, there is provided acarbamoylpyrrolidone derivative of the formula: ##STR4## (wherein R isphenoxy optionally substituted by a halogen, methoxy, or methyl group,##STR5## one of A and B is ##STR6## and the other is >CH₂ ; R¹ ishydrogen or C₁ -C₅ alkyl; Z¹ is phenyl, benzyl, or isoxazolyl eachoptionally substituted by a halogen, methoxy, or methyl group; Z² ishydrogen, C₁ -C₅ alkyl, C₂ -C₅ alkenyl, or phenyl optionally mono-, di-,or tri-substituted by a halogen, methoxy, or methyl group; or Z¹ and Z²taken together with the adjacent nitrogen atom may form 5-memberedheterocyclic group; Z³ is C₁ -C₅ hydroxyalkyl, di(C₁ -C₅alkyl)sulfamoyl, 6-membered heterocyclic group, phenyl, benzyl, orphenylsulfonyl each phenyl moiety of the last three members beingoptionally substituted by a halogen, methoxy, or methyl group; Z⁴ isphenyl optionally substituted by a halogen, methoxy, or methyl group or5- or 6-membered heterocyclic group which is optionally substituted by ahalogen, methoxy, or methyl group and which can be optionally condensedwith a benzene ring; Z⁵ is thienyl or phenyl each optionally substitutedby a halogen, methoxy, or methyl group; Z⁶ is thienyl or phenyl eachoptionally substituted by a halogen, methoxy, or methyl group; m is aninteger from 0 to 2; n is an integer from 2 to 3) or its pharmaceuticalacceptable acid addition salt.

The terms used in the above definition are explained below.

As the alkyl, methyl, ethyl, propyl, isopropyl, butyl, and pentyl areexemplified. As the alkoxy, methoxy, ethoxy, propoxy, isopropoxy,butoxy, and pentyloxy are exemplified. As the hydroxyalkyl,hydroxymethyl, hydroxyethyl, and hydroxybutyl are exemplified. As thedialkylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, anddibutylsulfamoyl are exemplified. As the halogen, fluorine, chlorine,bromine, and iodine are indicated. As the 5- or 6-membered heterocyclicgroup, isothiazolyl, pyrazolyl, pyrimidinyl, triazolyl, thiadiazolyl,imidazolyl, isoxazolyl, and pyridyl are illustrated.

The processes of producing Compound (I) are shown in the followingscheme. ##STR7## (wherein Ph is phenyl group; M is hydrogen or alkalimetal; and A, B, R, R¹, Z⁴, Z⁶, m, and n each has the same meaning asdefined above.)

Route A

Compound (I a) is obtained by reacting Compound (II) with a reagent(IV). In this reaction, no solvent is used and the reaction is carriedout at comparatively high temperature of 100°-150° C., preferably at115°-125° C. As the reagent (IV), 2-(4-methoxyphenylamino)ethylamine,2-(4-methylphenylamino)ethylamine, 2-(4-chlorophenylamino)ethylamine,1-aminoethylpyrazole, 2-(4-methoxyphenylamino)-N-methylethylamine,2-(4-methoxyphenyloxy)-N-methylethylamine,2-(4-methoxyphenyloxy)ethylamine, and2-(5-methylisoxazol-3-ylamino)ethylamine are exemplified.

Route B

The object compound (I a) is obtained by reacting Compound (III) withCompound (V). The reaction is carried out in an appropriate solvent at10°-120° C., preferably at 50°-100° C. As the solvent, benzene, dimethylsulfoxide, DMF, chloroform, ethyl acetate, and THF are illustrated. Ifnecessary, organic bases such as pyridine, triethylamine, anddimethylaniline; or inorganic bases such as K₂ CO₃, NaH, and NaOH may beadded as dehydrohalogenating agents. Also an alkali metal iodide such asNaI and KI may be used to accelerate the reaction.

Route C

Compound (I b) can be obtained by oxidizing Compound (I a) (when R=SZ⁴)with a suitable peracid. Generally, this reaction is carried out in anappropriate solvent at room temperature (1°-30° C.), preferably at10°-25° C. As the solvent, there are chloroform, CH₂ Cl₂, carbontetrachloride, ethyl acetate, and 1,2-dichloroethane, or a mixture ofsome of these solvents. As the peracid, peracetic acid, perbenzoic acid,and m-chloroperbenzoic acid (m-CPBA) are used.

Route D

Compound (I c) is obtained by subjecting Compound (I a) to dehydrationreaction, when R is ##STR8##

This reaction is carried out in an appropriate solvent in the presenceof dehydrating agents at the refluxing temperature of the solvent. Asthe solvent, toluene, dioxane, hexamethylphosphoramide, and ethylacetate are exemplified. As the dehydrating agent, phosphorus pentoxide,DCC, and Molecular Sieves are illustrated.

Route E

Compound (I d) is obtained by alkylating Compound (I a) (when R¹ =H)with a suitable alkylating agent. Generally, this reaction is carriedout in an appropriate solvent at room temperature (1°-30° C.),preferably at 10°-25° C. As the solvent, THF and ethyl acetate areillustrated. As the alkylating agent, methyl iodide, ethyl iodide, butylchloride, and allyl bromide are exemplified. In order to accelerate thereaction, a suitable base may be used. As the base, alkali metalhydroxide such as sodium hydroxide and potassium hydroxide; potassiumhydrogencarbonate, pyridine, triethylamine are exemplified.

The production of the starting materials (II) and (III) are shown in thefollowing scheme. ##STR9## (n is an integer of 2 or 3) (See ReferentialExamples 1-3)

The compounds (I) may be manufactured by any of the conventionalprocesses known in the chemical literature for the manufacture ofanalogous compounds.

The compound (I) can be converted into its pharmaceutically acceptableacid addition salt. Such acids illustratively include inorganic acidssuch as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid,hydrobromic acid, and hydrogen iodide and organic acids such as aceticacid, maleic acid, malic acid, citric acid, lactic acid, succinic acid,and methanesulfonic acid.

The objective compound (I) of this invention can be administered tohumans or animals orally or parenterally. For instance, Compound (I) canbe administered orally in the forms of tablets, granules, powder,capsules, solution, etc., or it is given parenterally in the forms ofinjection or suppositories. These preparations are manufactured in aknown process by using additives such as diluents, binders,disintegrators, lubricants, stabilizers, corrigents, suspenders,dispersants, solubilizers, and antiseptics.

As the diluents, lactose, sucrose, starch, cellulose, and sorbit; as thebinders, gum arabic, gelatin, and polyvinylpyrrolidone; and as thelubricants, magnesium stearate, talc, and silica gel are exemplified,respectively. When the objective compound (I) of this invention is usedfor the treatment of senile dementia, a daily dose of about 0.01 to 20mg/kg may be orally or parenterally administered once or in severaldivisions.

Embodiments of this invention are illustrated below by indicatingExamples, Referential Examples, and Preparations.

The abbreviations used in the Examples, Referential Examples and Tableshave the following meanings as mentioned below:

DMF: N,N-Dimethylformamide

m-CPBA: m-Chloroperbenzoic acid

THF: Tetrahydrofuran

EtI: Ethyl iodide

Et₂ O: Ether

Me: Methyl

Et: Ethyl

MeO: Methoxy

EtOH: Ethanol

i-PrOH: Isopropanol

MeOH: Methanol

DMA: N,N-Dimethylacetamide

hr.: hour

d.: day.

EXAMPLE 1 1-[[2-(4-Methoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine(I a-1) ##STR10##

To a solution of 1.0 g (5.24 mmol) of1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine and 0.646 g (5.24 mmol) ofp-anisidine in 15 ml of DMF were added 1.09 g (7.86 mmol) of K₂ CO₃ and0.30 g (2.00 mmol) of NaI, and the solution was heated with stirring at80°-85° C. for 40.5 hr. The reaction solution was mixed with ethylacetate, washed with water, dried, and concentrated. The residue wasrefined by silica gel chromatography, and 0.37 g (Yield 25.4%) of theobjective compound (I a-1) was obtained from the eluate withbenzene-ethyl acetate (3/1 v/v). The product obtained was washed withether -n-hexane and collected by filtration.

m.p.: 83.5°-84.5° C.

Anal. Calcd. (%) for C₁₄ H₁₉ N₃ O₃ : C, 60.63; H, 6.91; N, 15.15. Found(%): C, 60.65; H, 7.05; N, 15.30.

IR (CHCl₃): 3295, 2975, 1710, 1675 cm⁻¹.

NMR (CDCl₃): 2.00 (quint, J=7 Hz, 2H), 2.57 (t, J=7 Hz, 2H), 3.27 (t,J=6 Hz, 2H), 3.53 (q, J=6 Hz, 2H), 3.73 (s, 3H), 3.84 (t, J=7 Hz, 2H),6.59, 6.77 (A₂ B₂, J=9 Hz, 4H), 8.62(br., 1H).

EXAMPLES 2-29

The reactions were carried out in the same method as in Example 1mentioned above, whereby the compounds (I a) were obtained. The reactionconditions and their properties are shown in Tables 1 and 2,respectively.

                                      TABLE 1                                     __________________________________________________________________________     ##STR11##                                                                                                             Reaction                             III-1  Compound (V)          K.sub.2 CO.sub.3                                                                  NaI     Conditions                                                                             I a                         Ex.                                                                              g                     g   g   g   DMF     Temp.                                                                              Yield                                                                             Yield                                                                             Compd.              No.                                                                              (mmol)                                                                            Z.sup.1     Z.sup.2                                                                             (mmol)                                                                            (mmol)                                                                            (mmol)                                                                            (ml)                                                                              Time                                                                              (°C.)                                                                       (g) (%) No.                 __________________________________________________________________________     2  2.0 (10.5)                                                                        ##STR12##  Me     1.73 (12.6)                                                                       3.63 (26.2)                                                                       2.36 (15.8)                                                                      25  5 d.                                                                              100-105                                                                            2.00                                                                              65.4                                                                              I a-2                3  2.86 (15.0)                                                                       ##STR13##  Et     2.50 (16.5)                                                                       5.18 (37.5)                                                                       3.37 (22.5)                                                                      30  6 d.                                                                              100-105                                                                            2.10                                                                              45.8                                                                              I a-3                4  3.15 (16.5)                                                                       ##STR14##  n-Pr   3.00 (18.2)                                                                       5.70 (41.3)                                                                       3.71 (24.8)                                                                      35  7 d.                                                                              100-105                                                                            2.23                                                                              42.2                                                                              1 a-4                5  2.0 (10.5)                                                                        ##STR15##  H      1.60 (10.5)                                                                       2.16 (15.7)                                                                       1.0 (6.67)                                                                       30  8 d.                                                                               95-100                                                                            0.64                                                                              20.0                                                                              I a-5                6  3.0 (15.7)                                                                        ##STR16##  H      2.88 (15.7)                                                                       3.24 (23.6)                                                                       3.54 (23.6)                                                                      35  5 d.                                                                               95-100                                                                            2.59                                                                              49.0                                                                              I a-6                7  3.0 (15.7)                                                                        ##STR17##  H      2.52 (23.5)                                                                       3.22 (23.5)                                                                       3.52 (23.5)                                                                      35  4 d.                                                                              85   1.15                                                                              28.0                                                                              I a-7                8  1.6 (8.39)                                                                        ##STR18##  Me    1.037 (8.56)                                                                       1.96 (14.3)                                                                       0.3 (2.0)                                                                        20  4.6 d.                                                                             80-90                                                                             1.26                                                                              54.5                                                                              I a-8                9  2.86 (15.0)                                                                       ##STR19##                                                                                 ##STR20##                                                                           3.02 (16.5)                                                                       5.18 (37.5)                                                                       3.37 (22.5)                                                                      30  12 d.                                                                             100-105                                                                            0.60                                                                              11.9                                                                              I a-9               10  1.50 (7.87)                                                                       ##STR21##  H      1.08 (7.87)                                                                       1.63 (11.8)                                                                       1.60 (10.7)                                                                      20  2.9 d. 20 hr.                                                                      55-60  95-100                                                                     0.89                                                                              20.2                                                                              I a-10              11  3.60 (18.9)                                                                       ##STR22##  H      2.40 (19.8)                                                                       6.53 (47.3)                                                                       4.25 (28.4)                                                                      35  4.5 d.                                                                             85-90                                                                             1.62                                                                              31.1                                                                              I a-11              12  1.50 (7.87)                                                                       ##STR23##  H      1.11 (7.87)                                                                       1.63 (11.8)                                                                       1.6 (10.7)                                                                       20  2.8 d. 17 hr.                                                                      55-60 100                                                                         1.36                                                                              25.2                                                                              I a-12              13  2.0 (10.5)                                                                        ##STR24##  H      2.14 (10.5)                                                                       5.10 (36.8)                                                                       0.79 (5.25)                                                                      30  7.5 d.                                                                             80-90                                                                             0.98                                                                              14.5                                                                              I a-13              14  3.0 (15.7)                                                                        ##STR25##         2.90 (16.5)                                                                       3.24 (23.6)                                                                       3.54 (23.6)                                                                      30  2.2 d.                                                                             90-95                                                                             2.87                                                                              55.2                                                                              I a-14              15  3.0 (15.7)                                                                        ##STR26##          2.67 (16.5)                                                                      3.24 (23.6)                                                                       3.54 (23.6)                                                                      30  3.2 d.                                                                             95-100                                                                            3.50                                                                              70.3                                                                              I a-15              16  3.0 (15.7)                                                                        ##STR27##         3.54 (23.6)                                                                       3.24 (23.6)                                                                       3.54 (23.6)                                                                      30  3.8 d.                                                                             90-95                                                                             4.58                                                                              84.0                                                                              I a-16              17  1.91 (10.02)                                                                      ##STR28##         2.30 (10.06)                                                                      2.25 (15.0)                                                                       2.86 (15.0)                                                                      20  2.9 d.                                                                             90-95                                                                             1.68                                                                              48.4                                                                              I a-17              18  1.91 (10.02)                                                                      ##STR29##         2.37 (10.0)                                                                       4.1 (30.0)                                                                        2.25 (15.0)                                                                      30  5 d.                                                                               90-95                                                                             1.18                                                                              37.0                                                                              I a-18              19  5.0 (26.2)                                                                        ##STR30##          3.76 (28.9)                                                                      7.24 (52.4)                                                                       5.89 (39.3)                                                                      50  5 d.                                                                              90   4.38                                                                              58.8                                                                              I a-19              20  1.50 (7.89)                                                                       ##STR31##         2.16 (8.28)                                                                       2.18 (1.58)                                                                       1.77 (1.18)                                                                      20  4 d.                                                                              100-105                                                                            1.66                                                                              50.8                                                                              I a-20              21  1.64 (8.60)                                                                       ##STR32##         2.21 (9.03)                                                                       2.38 (17.2)                                                                       1.93 (12.9)                                                                      25  3.8 d.                                                                            100-105                                                                            1.10                                                                              32.1                                                                              I a-21              22  1.64 (8.60)                                                                       ##STR33##         2.36 (9.21)                                                                       2.38 (17.2)                                                                       1.93 (12.9)                                                                      25  4 d.                                                                              100-105                                                                            0.65                                                                              50.8                                                                              I a-22              23  2.42 (12.7)                                                                       ##STR34##         2.80 (14.5)                                                                       3.51  (25.4)                                                                      2.86 (19.1)                                                                      30  5 d.                                                                              100  2.02                                                                              45.8                                                                              I a-23              24  2.30 (12.1)                                                                       ##STR35##         2.93 (12.7)                                                                       3.32 (24.2)                                                                       2.72 (18.2)                                                                      25  3.2 d.                                                                            100  3.29                                                                              65.5                                                                              I a-24              25  0.89 (4.67)                                                                       ##STR36##         0.99 (4.68)                                                                       0.97 (7.02)                                                                       1.05 (7.01)                                                                      10  2.9 d.                                                                             90-95                                                                             1.48                                                                              86.6                                                                              I a-25              26  3.00 (15.7)                                                                       ##STR37##         2.82 (17.3)                                                                       5.38 (39.2)                                                                       3.53 (23.5)                                                                      55  5 d.                                                                              115  3.1 62.0                                                                              I a-26              27  2.56 (13.4)                                                                       ##STR38##         2.50 (14.1)                                                                       4.63 (33.5)                                                                       3.0 (20.1)                                                                       30  3 d.                                                                              100-105                                                                            3.07                                                                              69.0                                                                              I a-27              28  1.15 (6.03)                                                                       ##STR39##         1.25 (6.03)                                                                       2.08 (15.1)                                                                       1.36 (9.04)                                                                      20  3 d.                                                                              100-105                                                                            1.65                                                                              75.7                                                                              I a-28              29  0.96 (5.06)                                                                       ##STR40##         1.0 (5.16)                                                                        1.75 (12.6)                                                                       1.14 (7.59)                                                                      20  3.75 d.                                                                           100-105                                                                            0.34                                                                              19.4                                                                              I a-29              30  2.81 (14.7)                                                                       ##STR41##         2.70 (14.7)                                                                       6.10 (44.1)                                                                       3.30 (22.0)                                                                      30  4 d.                                                                              100-105                                                                            3.89                                                                              78.2                                                                              I a-30              31  2.08 (10.9)                                                                       ##STR42##         2.00 (10.9)                                                                       4.52 (32.7)                                                                       2.45 (16.4)                                                                      30  4 d.                                                                              100-105                                                                            1.91                                                                              51.9                                                                              I a-31              32  2.79 (14.6)                                                                       ##STR43##         3.10 (14.6)                                                                       6.05 (43.8)                                                                       3.28 (21.9)                                                                      35  5 d.                                                                              100-105                                                                            4.25                                                                              79.4                                                                              I a-32              33  1.80 (9.46)                                                                       ##STR44##         1.72 (8.53) (.HCL  salt)                                                          3.92 (2.84)                                                                       2.13 (1.42)                                                                      30  4 d.                                                                              100-105                                                                            2.38                                                                              87.4                                                                              I                   __________________________________________________________________________                                                              a-33            

                                      TABLE 2                                     __________________________________________________________________________    Com-                                                                              m.p. (°C.)                                                         pound                                                                             (Recrystalli-                                                                        Elementary Analysis                                                                       IR (cm.sup.-1)                                         No. zing solvent)                                                                        Found (Calcd.) (%)                                                                        (CHCl.sub.3)                                                                          NMR (CDCl.sub.3) δ                       __________________________________________________________________________    Ia-2                                                                              84.5-85.5                                                                            C.sub.15 H.sub.21 N.sub.3 O.sub.3                                                         3300, 1705, 1680                                                                      1.75-2.15 (m, 2H), 2.55 (t, J=7Hz, 2H),            (Et.sub.2 O)                                                                         C, 61.73 (61.84)                                                                          1540, 1510                                                                            2.90 (s, 3H), 3.40 (s, 4H), 3.74 (s,                      H,  7.26  (7.27)    3H), 3.80 (t, J=7Hz, 2H), 6.80 (s, 4H),                   N, 14.39 (14.42)    8.50 (br., 1H)                                 Ia-3                                                                              87.0-88.5                                                                            C.sub.16 H.sub.23 N.sub.3 O.sub.3                                                         3300, 1705, 1670                                                                      1.10 (t, J=7Hz, 3H), 1.80-2.16 (m, 2H),            (Et.sub.2 O)                                                                         C, 62.93 (62.93)                                                                          1530 (sh), 1505                                                                       2.57 (t, J=7Hz, 2H), 3.28 (q, J=7Hz,                      H,  7.64  (7.59)    2H), 3.36 (s, 3H), 3.83 (t, J=7Hz, 2H),                   N, 13.73 (13.76)    6.80 (s, 4H), 8.54 (br., 1H)                   Ia-4                                                                              70.0-71.0                                                                            C.sub.17 H.sub.25 N.sub.3 O.sub.3                                                         3280, 1700, 1670                                                                      0.90 (t, J= 7Hz, 3H), 1.55 (quint, J=7Hz,          (Et.sub.2 O)                                                                         C, 64.09 (63.92)                                                                          1530 (sh), 1500                                                                       2H), 2.00 (quint, J=7Hz, 2H), 2.56 (t,                    H,  7.90  (7.89)    J=7Hz, 2H), 3.16 (t, J=7Hz, 2H), 3.33                     N, 13.18 (13.16)    (s, 4H), 3.73 (s, 3H), 3.83 (t, J=7Hz,                                        2H), 6.80 (s, 4H), 8.54 (br., 1H)              Ia-5                                                                              --     C.sub.15 H.sub.21 N.sub.3 O.sub.4                                                         3300, 1710, 1680                                                                      2.00 (quint, J=7Hz, 2H), 2.57 (t, J=7Hz,                  C, 58.53 (58.62)                                                                          1615, 1600                                                                            2H), 3.20-3.60 (m, 4H), 3.73 (s, 3H),                     H,  6.84  (6.89)                                                                          1540 (sh), 1520                                                                       3.78 (s, 3H), 3.85 (t, J=7Hz, 2H), 4.50                   N, 13.46 (13.67)    (br., 1H), 6.13 (dd, J.sub.1 =9Hz, J.sub.2                                    =2Hz, 1H)                                                                     6.23 (d, J=2Hz, 1H), 6.64 (d, J=9Hz,                                          1H), 8.60 (br., 1H)                            Ia-6                                                                              124.0-125.5                                                                          C.sub.16 H.sub.23 N.sub.3 O.sub.5                                                         3290, 1700, 1665                                                                      2.00 (quint, J=7Hz, 2H), 2.57 (t, J=7Hz,           (EtOH) C, 56.96 (56.96)                                                                          1600, 1535, 1500                                                                      2H), 3.29 (q, J=6Hz, 2H), 3.51 (q, J=6Hz,                 H,  6.85  (6.87)    2H), 3.71 (s, 3H), 3.80 (s, 6H), 3.84 (t,                 N, 12.32 (12.46)    J=7Hz, 2H) 5.85 (s, 2H), 8.60 (br., 1H)        Ia-7                                                                              maleate                                                                              C.sub.14 H.sub.19 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                 (free base)                                                                           (free base)                                        143.0-144.0                                                                          C, 57.17 (57.28)                                                                          3290, 1700, 1670                                                                      1.80-2.13 (m, 2H), 2.56 (t, J=7H, 2H),                                        2.79                                               (i-PrOH)                                                                             H,  6.32  (6.14)                                                                          1535    (t, J=6Hz, 2H), 3.40 (q, J=6Hz, 2H), 3.80                 N, 11.12 (11.14)    (s, 2H), 3.80 (t, J=7Hz, 2H), 7.30 (s,                                        5H),                                                                          8.60 (br., 1H)                                 Ia-8                                                                              maleate                                                                              C.sub.15 H.sub.21 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                 (free base)                                                                           (free base)                                        130.0-130.5                                                                          C, 58.24 (58.30)                                                                          3300, 1705, 1675                                                                      2.00 (quint, J=7Hz, 2H), 2.48-2.70 (m,                                        4H),                                               (i-PrOH)                                                                             H,  6.46  (6.44)                                                                          1530    2.87 (s, 3H), 3.43 (q, J=6Hz, 2H), 3.54                                       (s,                                                       N, 10.70 (10.74)    2H), 3.83 (t, J=7Hz, 2H), 7.20-7.40 (m,                                       5H),                                                                          8.67 (br., 1H)                                 Ia-9                                                                              97.0-98.0                                                                            C.sub. 20 H.sub.23 N.sub.3 O.sub.2                                                        3290, 1705, 1675                                                                      1.98 (quint, J=7Hz, 2H), 2.56 (t, J=7Hz,                                      2H)                                                (Et.sub.2 O)                                                                         C, 71.19 (71.19)                                                                          1590, 1530, 1500                                                                      3.58 (s, 4H), 3.81 (t, J=7Hz, 2H), 4.59                                       (s,                                                       H,  6.91  (6.87)    2H), 6.60-7.30 (m, 10H), 8.53 (br., 1H)                   N, 12.49 (12.45)                                                   Ia-10                                                                             maleate                                                                              C.sub.15 H.sub.21 N.sub.3 O.sub.3.C.sub.4 H.sub.4 O.sub.4                                 (free base)                                                                           (free base)                                        142.5-143.5                                                                          C, 55.98 (56.01)                                                                          3300, 1710, 1680                                                                      1.80-2.15 (m, 2H), 2.57 (t, J=7Hz, 2H),                                       2.77                                               (i-PrOH)                                                                             H,  6.25  (6.19)                                                                          1610, 1580, 1540                                                                      (t, J=6Hz, 2H), 3.40 (q, J=6Hz, 2H), 3.76                 N, 10.27 (10.31)                                                                          1505    (s, 3H), 3.80 (t, J=7Hz, 2H), 6.85, 7.23                                      (A.sub.2 B.sub.2, J=9Hz, 4H), 8.60 (br.,                                      1H)                                            Ia-11                                                                             maleate                                                                              C.sub.15 H.sub.21 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                 (free base)                                                                           (free base)                                        155.0-156.0                                                                          C, 58.11 (58.30)                                                                          3290, 1700, 1670                                                                      1.98 (quint, J=7Hz, 2H), 2.30 (s, 3H),                                        2.55                                               (i-PrOH)                                                                             H,  6.43  (6.44)                                                                          1535    (t, J= 7Hz, 2H), 2.77 (t, J=6Hz, 2H),                                         3.39                                                      N, 10.68 (10.74)    (q, J=6Hz, 2H), 3.75 (s, 2H), 3.80 (t,                                        J=7Hz                                                                         2H), 7.10, 7.20 (A.sub.2 B.sub.2, J=9Hz,                                      4H), 8.58                                                                     (br., 1H)                                      Ia-12                                                                             maleate                                                                              C.sub.14 H.sub.18 N.sub.3 O.sub.2 Cl.                                                     (free base)                                                                           (free base)                                        161.5-162.0                                                                          C.sub.4 H.sub.4 O.sub.4                                                                   3300, 1705, 1675                                                                      1.99 (quint, J=7Hz, 2H), 2.57 (t, J=7Hz,                                      2H)                                                (i-PrOH)                                                                             C, 52.47 (52.50)                                                                          1540    2.75 (t, J=6Hz, 2H), 3.39 (q, J=6Hz, 2H),                 H,  5.31  (5.38)    3.75 (s, 2H), 3.80 (t, J=7Hz, 2H), 7.28                                       (s,                                                       N, 10.26 (10.20)    4H), 8.60 (br., 1H)                                       Cl, 8.69  (8.61)                                                   Ia-13                                                                             --     C.sub.16 H.sub.23 N.sub.3 O.sub.4.                                                        3300, 1705, 1670                                                                      1.97 (quint, J=7Hz, 2H), 2.54 (t, J=7Hz,                                      2H)                                                        1/5 CH.sub.2 Cl.sub.2                                                                    1610, 1580, 1545                                                                      2.80 (t, J=6Hz, 2H), 3.47 (q, J=6Hz, 2H),                 C, 57.59 (57.51)                                                                          1500    3.74 (s, 2H), 3.78 (t, J=7Hz, 2H), 3.80                                       (s,                                                       H,  7.06  (6.97)    6H), 6.43 (br., 2H), 7.20 (d, J=9Hz, 1H),                 N, 12.66 (12.42)    8.60 (br., 1H)                                 Ia-14                                                                             80.5-81.5                                                                            C.sub.18 H.sub.26 N.sub.4 O.sub.2                                                         3300, 1705, 1670                                                                      2.00 (quint, J=7Hz, 2H), 2.45-2.70 (m,                                        12H),                                              (Et.sub.2 O-                                                                         C, 65.52 (65.43)                                                                          1540, 1520 (sh)                                                                       3.40 (q, J=6Hz, 2H), 3.50 (s, 2H), 3.84                                       (t,                                                n-Hexane =                                                                           H,  7.97  (7.93)    J=7Hz, 2H), 7.30 (s, 5H), 8.63 (br., 1H)           2:1v/v)                                                                              N, 16.94 (16.96)                                                   Ia-15                                                                             133.0-134.0                                                                          C.sub.17 H.sub.24 N.sub.4 O.sub.2                                                         3280, 1700, 1670                                                                      2.00 (quint, J=7Hz, 2H), 2.50-2.70 (m,                                        8H),                                               (Et.sub.2 O -                                                                        C, 64.52 (64.53)                                                                          1590, 1520, 1485                                                                      3.13-3.27 (m, 4H), 3.45 (q, J=6Hz, 2H),                                       3.84                                               n-Hexane =                                                                           H,  7.60  (7.65)    (t, J=7Hz, 2H), 6.73-7.00 (m, 3H),                                            7.13-7.30                                          1:1v/v)                                                                              N, 17.62 (17.71)    (m, 2H), 8.65 (br., 1H)                        Ia-16                                                                             maleate                                                                              C.sub.18 H.sub.26 N.sub.4 O.sub.3.                                                        (free base)                                                                           (free base)                                        180.0-183.0                                                                          C.sub.4 H.sub.4 O.sub.4                                                                   3300, 1700, 1665                                                                      1.97 (quint, J=7Hz, 2H), 2.45-2.70 (m,                                        6H),                                               (d)    C, 57.03 (57.13)                                                                          1580, 1520, 1490                                                                      3.04-3.20 (m, 4H), 3.45 (q, J=6Hz, 2H),                                       3.82                                               (i-PrOH-                                                                             H,  6.72  (6.54)    (t, J=7Hz, 2H), 3.84 (s, 3H), 6.92 (s,                                        4H),                                               MeOH)  N, 12.14 (12.12)    8.65 (br., 1H)                                 Ia-17                                                                             124.5-125.5                                                                          C.sub.18 H.sub.26 N.sub.4 O.sub.3                                                         3300, 1705, 1670                                                                      2.00 (quint, J=7Hz, 2H), 2.50-2.70 (m,                                        8H),                                               (Et.sub.2 O-                                                                         C, 62.43 (62.41)                                                                          1540 (sh), 1505                                                                       3.05-3.17 (m, 4H), 3.47 (q, J=6Hz, 2H),                                       3.75                                               Ch.sub.2 Cl.sub.2)                                                                   H,  7.48  (7.56)    (s, 3H), 3.85 (t, J=7Hz, 2H), 6.87                                            (A.sub.2 B.sub.2, J=                                      N, 16.31 (16.17)    9Hz, 4H), 8.67 (br., 1H)                       Ia-18                                                                             80.5-81.5                                                                            C.sub.15 H.sub.22 N.sub.6 O.sub.2                                                         3300, 1705, 1670                                                                      2.01 (quint, J=7Hz, 2H), 2.47-2.70 (m,                                        8H),                                               (Et.sub.2 O)                                                                         C, 56.62 (56.59)                                                                          1580, 1540, 1500                                                                      3.45 (q, J=6Hz, 2H), 3.75-3.93 (m, 6H),                                       6.45                                                      H,  6.94  (6.96)                                                                          1485 (sh)                                                                             (t, J=5Hz, 1H), 8.27 (d, J=5Hz, 2H), 8.68                 N, 26.28 (26.40)    (br., 1H)                                      Ia-19                                                                             109.0-111.0                                                                          C.sub.13 H.sub.24 N.sub.4 O.sub.3                                                         3300, 1705, 1675                                                                      2.02 (quint, J=7Hz, 2H), 2.47-2.70 (m,                                        14H),                                              (Et.sub.2 O)                                                                         C, 54.68 (54.91)                                                                          1520    3.04 (s, 1H), 3.40 (q, 6Hz, 2H), 3.62 (t,                                     J=                                                        H,  8.40  (8.51)    6Hz, 2H), 3.87 (t, J=7Hz, 2H), 8.64 (br.,                 N, 19.56 (19.71)    1H)                                            Ia-20                                                                             149.0-150.0                                                                          C.sub.17 H.sub.23 N.sub.4 O.sub.4 SCl                                                     3290, 1700, 1670                                                                      2.00 (quint, J=7Hz, 2H), 2.45-2.65 (m,                                        8H),                                               (EtOH) C, 49.09 (49.21)                                                                          1580, 1530                                                                            3.00-3.13 (m, 4H), 3.37 (q, J=6Hz, 2H),                                       3.82                                                      H,  5.49  (5.59)    (t, J=7Hz, 2H), 7.53-7.74 (A.sub.2                                            B.sub.2, J=9Hz, 4H)                                       N, 13.35 (13.50)    8.52 (br., 1H)                                            S,  7.71  (7.73)                                                              Cl, 8.40  (8.54)                                                   Ia-21                                                                             110.5-111.5                                                                          C.sub.17 H.sub.23 N.sub.4 O.sub.4 SF                                                      3300, 1705, 1675                                                                      1.85-2.16 (m, 2H), 2.46-2.60 (m, 8H),              (EtOH) C, 51.05 (51.24)                                                                          1590, 1525, 1490                                                                      3.00-3.12 (m, 4H), 3.36 (q, J=6Hz, 2H),                                       3.81                                                      H,  5.59   (5.82)   (t, J=7Hz, 2H), 7.22 (t, J=9Hz, 2H), 7.78                 N, 13.87 (14.06)    (d-d, J.sub.1 =9Hz, J.sub.2 =6Hz, 2H),                                        8.52 (br., 1H)                                            S,  8.26  (8.05)                                                              F,  5.03  (4.77)                                                   Ia-22                                                                             186.5-187.5                                                                          C.sub.18 H.sub.26 N.sub.4 O.sub.5 S                                                       3310, 1705, 1675                                                                      1.80-2.15 (m, 2H), 2.40-2.65 (m, 8H),                                         2.96-                                              (EtOH) C, 52.52 (52.67)                                                                          1595, 1575, 1530                                                                      3.08 (m, 4H), 3.35 (q, J=6Hz, 2H), 3.80                                       (t,                                                       H,  6.39  (6.38)                                                                          1490    J=7Hz, 2H), 8.85 (s, 3H), 7.00, 7.65                                          (A.sub.2 B.sub.2,                                         N, 13.53 (13.65)    J=9Hz, 4H), 8.47 (br., 1H)                                S,  7.84  (7.81)                                                   Ia-23                                                                             97.0-97.5                                                                            C.sub.13 H.sub.25 N.sub.5 O.sub.4 S                                                       3290, 1700, 1670                                                                      1.83-2.17 (m, 2H), 2.40-2.67 (m, 8H),                                         2.80                                               (EtOH) C, 44.87 (44.97)                                                                          1520    (s, 6H), 3.20-3.50 (m, 6H), 3.83 (t,                                          J=7Hz,                                                    H,  7.15  (7.25)    2H), 8.62 (br., 1H)                                       N, 20.13 (20.16)                                                              S,  9.13  (9.23)                                                   Ia-24                                                                             195.0-200.0                                                                          C.sub.20 H.sub.27 N.sub. 5 O.sub.3.C.sub.2 H.sub.5 OH                                     3425, 3270, 1710                                                                      1.64-2.20 (m, 4H), 2.53-2.85 (m, 10H),                                        3.44                                               (EtOH) C, 61.18 (61.23)                                                                          1675, 1600, 1515                                                                      (q, J=6Hz, 2H), 3.86 (t, J=7Hz, 2H), 4.73                 H,  7.49  (7.71)                                                                          1495    (s, 2H) 6.70-7.40 (m, 5H), 7.64 (br. s,                                       1H),                                                      N, 16.84 (16.23)    8.88 (br., 1H)                                 Ia-25                                                                             152.5-153.5                                                                          C.sub.18 H.sub.24 N.sub.3 O.sub.3 Cl                                                      3580, 3300, 1705                                                                      1.62-2.30 (m, 6H), 2.40-2.85 (m, 8H),                                         3.42                                               (Et.sub.2 O-                                                                         C, 58.87 (59.09)                                                                          1670, 1525                                                                            (q, J=6Hz, 2H), 3.80 (t, J=7Hz, 2H),                                          7.29,                                              CH.sub.2 Cl.sub.2)                                                                   H,  6.54  (6.61)    7.43 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.65                                       (br., 1H)                                                 N, 11.28 (11.49)                                                              Cl, 9.52  (9.69)                                                   Ia-26                                                                             dimaleate                                                                            C.sub.16 H.sub.23 N.sub.5 O.sub.2.                                                        (Nujol) (free base)                                        149.0-150.0                                                                          2C.sub.4 H.sub.4 O.sub.4                                                                  dimaleate                                                                             1.85-2.17 (m, 2H), 2.50-2.63 (m, 6H),                                         3.35-                                              (MeOH- C, 52.2  (52.45)                                                                          3310, 1715, 1680                                                                      3.60 (m, 6H), 3.84 (t, J=7Hz, 2H),                                            6.50-6.73                                          i-PrOH)                                                                              H,  5.75  (5.69)                                                                          1630, 1610                                                                            (m, 2H), 7.28-7.55 (m, 1H), 8.17 (d-d,                                        J.sub.1 =                                                 N, 12.69 (12.75)    9Hz, J.sub.2 =2Hz, 1H), 8.69 (br., 1H)         Ia-27                                                                             113.0-114.0                                                                          C.sub.18 H.sub.25 N.sub.3 O.sub.3                                                         3260, 2910, 1705                                                                      1.70-2.90 (m, 16H), 3.45 (q, J=6Hz, 2H),           (EtOH) C, 65.29 (65.23)                                                                          1670, 1520                                                                            3.85 (t, J=7Hz, 2H), 7.36, 5.51 (A.sub.2                                      B.sub.2,                                                  H,  7.61  (7.60)    J=9Hz, 4H), 8.66 (br., 1H)                                N, 12.67 (12.68)                                                   Ia-28                                                                             105.5-106.5                                                                          C.sub.19 H.sub.27 N.sub.3 O.sub.4                                                         3290, 2930, 1705                                                                      1.68-2.85 (m, 15H), 3.43 (q, J=6Hz, 2H),           (1-PrOH)-                                                                            C, 63.02 (63.14)                                                                          1675, 1610, 1505                                                                      3.79 (s, 3H), 3.82 (t, J=7Hz, 2H), 6.86,           Et.sub.2 O)                                                                          H,  7.58  (7.53)    7.43 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.64                                       (br., 1H)                                                 N, 11.47 (11.63)                                                   Ia-29                                                                             141.5-142.5                                                                          C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl                                                      3290, 2895, 1700                                                                      2.03 (quint, J=7Hz, 2H), 2.50-2.80 (m,                                        8H),                                               (i-PrOH)                                                                             C, 62.24 (62.15)                                                                          1670, 1530                                                                            3.21 (q, J=3Hz, 2H), 3.51 (q, J=6Hz, 2H),                 H,  6.36  (6.37)    3.87 (q, J=7Hz, 2H), 6.06 (br., 1H),                                          7.20-                                                     N, 12.05 (12.08)    7.37 (m, 4H), 8.60 (br., 1H)                              Cl, 10.23 (10.19)                                                  Ia-30                                                                             126.0-126.5                                                                          C.sub.16 H.sub.23 N.sub.3 O.sub.3 S                                                       3560, 3350, 1705                                                                      1.90-2.30 (m, 7H), 2.50-2.80 (m, 8H),              (CH.sub.2 Cl.sub.2 -                                                                 C, 56.89 (56.95)                                                                          1670, 1530                                                                            3.443 (q, J=5.4Hz, 2H), 3.857 (t,                                             J=7.2Hz,                                           Et.sub.2 O)                                                                          H,  6.84  (6.87)    2H), 6.90-7.30 (m, 3H), 8.650 (br., 1H)                   N, 12.41 (12.45)                                                              S,  9.41  (9.50)                                                   Ia-31                                                                             tartrate                                                                             C.sub.16 H.sub.23 N.sub.3 O.sub.3 S.                                                      (Nujol) (free base)                                        powder C.sub.4 H.sub.6 O.sub.6 1/2H.sub.2 O                                                      L-tartrate                                                                            1.65-1.90 (m, 2H), 1.95-2.15 (m, 5H),                     C, 48.62 (48.38)                                                                          3380, 3280, 1700                                                                      2.417, 2.881 (ABq, J=11Hz, 2H), 2.55-2.65                 H,  6.18  (6.09)                                                                          1670, 1600, 1535                                                                      (m, 4H), 2.934 (d, J=10Hz, 1H), 3.30-3.50                 N,  8.12  (8.46)    (m, 2H), 3.855 (t, J=7Hz, 2H), 4.219                      S,  6.33  (6.46)    (s, 1H), 6.954-6.973 (m, 2H), 7.182-7.222                                     (m, 1H), 8.918 (br. s, 1H)                     Ia-32                                                                             119.5-120.5                                                                          C.sub.18 H.sub.24 N.sub.3 O.sub.3 Cl                                                      3500, 3280, 1705                                                                      1.65-2.15 (m, 7H), 2.404 (a part of ABq,           (Et.sub.2 O-                                                                         C, 59.11 (59.09)                                                                          1675, 1545, 1525                                                                      J=11Hz, 1H), 2.55-2.75 (m, 5H), 2.975 (d,          toluene)                                                                             H,  6.45  (6.61)                                                                          1485    J=10Hz, 1H), 3.418 (m, 2H), 3.867 (t,                                         J=7Hz,                                                    N, 11.49 (11.49)    2H), 4.162 (s, 1H), 7.272-7.501 (m, 3H),                  Cl, 9.96  (9.96)    8.929 (br., 1H)                                Ia-33                                                                             tartrate                                                                             C.sub.16 H.sub.21 N.sub.3 O.sub.2 S.                                                      (Nujol) (free base)                                        powder C.sub.4 H.sub.6 O.sub.6 1/2H.sub.2 O                                                      L-tartrate                                                                            2.020 (quint, J=7Hz, 2H), 2.355 (s, 2H)                   C, 49.78 (50.20)                                                                          3260, 1700, 1670                                                                      2.590 (t, J=7Hz, 2H), 2.63-2.75 (m, 6H),                  H,  5.82  (5.90)                                                                          (sh), 1650 (sh),                                                                      3.37-3.40 (m, 2H), 3.518 (q, J=6Hz, 2H),                  N,  8.33  (8.78)                                                                          1590, 1525                                                                            3.858 (t, J=7Hz, 2H), 6.16-6.20 (m, 1H),                  S,  6.37  (6.70)    6.88-7.19 (m, 3H)                              __________________________________________________________________________

EXAMPLE 34 2-Oxo-1-[[2-(1,2,4-triazol-1-yl)ethyl]carbamoyl]pyrrolidine(I a-34) ##STR45##

To a solution of 1.9 g (27.5 mmol) of 1,2,4-triazole in 15 ml of DMF wasadded 1.1 g (27.5 mmol) of 60% NaH, and the mixture was heated at 90° C.for about 2 hr. Then, 13 ml of DMF containing 3.50 g (18.4 mmol) of1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was added to themixture, which was heated at 90° C. for 4.5 hr. The reaction solutionwas poured into CH₂ Cl₂, and the insoluble material was removed byfiltration. After evaporating the solvent, the CH₂ Cl₂ layer was refinedby silica gel column chromatography, whereby 2.28 g (55.6%) of theobjective compound (I a-34) was obtained from the eluate with CH₂ Cl₂-methanol (20/1 v/v). The crystals melting at 106.0°-107.0° C. wereobtained by recrystalling from ethanol.

Anal. Calcd. (%) for C₉ H₁₃ N₅ O₂ : C, 48.42; H, 5.87; N, 31.38. Found(%): C, 48.47; H, 5.77; N, 31.19. IR (CHCl₃): 3300, 1710, 1685, 1530,1505 (sh), 1485, 1455, 1430 cm⁻¹.

NMR (CDCl₃): 1.85-2.20 (m, 2H), 2.58 (t, J=7 Hz, 2H), 3.65-3.90 (m, 4H),4.37 (t, J=7 Hz, 2H), 7.97 (s, 1H), 8.08 (s, 1H), 8.55 (br., 1H).

EXAMPLE 35 2-Oxo-1-[[2-(1H-imidazol-1-yl)ethyl]carbamoyl]pyrrolidine (Ia-35) ##STR46##

In the same method as in Example 34 described above, 3.0 g (15.7 mmol)of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was reactedwith a solution of 1.29 g (18.9 mmol) of 1H-imidazole in 24 ml of DMF at110° C. for 6.5 hr. in the presence of 0.75 g (18.9 mmol) of 60% NaH,whereby the compound (I a-35) was obtained.

Yield: 1.22 g; 34.9%.

m.p.: 130.5°-131.5° C. (Et₂ O).

Anal. Calcd. (%) for C₁₀ H₁₄ N₄ O₂ : C, 54.04; H, 6.35; N, 25.21. Found(%): C, 53.89; H, 6.29; N, 25.00.

IR (CHCl₃): 3300, 1710, 1680 (sh), 1540, 1510 (sh) cm⁻¹.

NMR (CDCl₃): 1.86-2.20 (m, 2H), 2.60 (t, J=7 Hz, 2H), 3.60 (q, J=6 Hz,2H), 3.83 (t, J=7 Hz, 2H), 4.12 (t, J=6 Hz, 2H), 6.95 (s, 1H), 7.07 (s,1H), 7.48 (s, 1H), 8.55 (br., 1H).

EXAMPLE 36 1-[[2-(4-Methoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine(I a-1) ##STR47##

A mixture of 4.0 g (19.5 mmol) of 1-phenoxycarbonyl-2-oxopyrrolidine and3.4 g (20.4 mmol) of 2-(4-methoxyphenylamino)ethylamine was heated at115°-120° C. for 4 hr. The reaction solution was refined by silica gelcolumn chromatography, whereby 4.94 g (87.0%) of the objective product(I a-1) was obtained from the eluate with toluene-ethyl acetate (3/1v/v). The needles melting at 83.5°-84.5° C. were obtained byrecrystallizing from ethanol.

EXAMPLES 37-38

The reactions were carried out in the same method as in Example 36described above. The reaction conditions and their properties of eachobjective compounds are shown in Tables 3 and 5, respectively.

                                      TABLE 3                                     __________________________________________________________________________     ##STR48##                                                                                               Reaction                                              Compound                Conditions                                                                           Compound (I a)                                                                        Com-                                Ex.                                                                              (II)  Compound (IV)     Temp. (°C.)                                                                   Yield   pound                               No.                                                                              g (mmol)                                                                            R            g (mmol)                                                                           Time   (g) (%) No.                                 __________________________________________________________________________    37  2.86 (13.9)                                                                         ##STR49##    2.2 (14.6)                                                                        115-120 5.5 hr.                                                                      3.21                                                                              88.1                                                                              I a-36                              38  2.18 (10.6)                                                                         ##STR50##    2.0 (11.7)                                                                        120-125 4 hr.                                                                        2.88                                                                              96.0                                                                              I a-37                              __________________________________________________________________________

EXAMPLE 39 1-[[2-(Pyrazol-1-yl)ethyl]carbamoyl]-2-oxopyrrolidine (Ia-38)

To a solution of 3.58 g (14.8 mmol) of 2-phthalimidoethylpyrazole in 45ml of methanol was added 1.11 g (22.2 mmol) of hydrazine hydrate, andthe mixture was refluxed for 7 hr. The solvent was evaporated underreduced pressure, and the residue was washed with CH₂ Cl₂ and ethylacetate, and filtered. The filtrate was evaporated under reducedpressure, and then 2.73 g (13.3 mmol) of2-oxo-1-phenoxycarbonylpyrrolidine (II) was added to the residue, andthe mixture was heated at 115°-120° C. for 3 hr. After cooling, thereaction mixture was refined by silica gel column chromatography, andthe resulting crystalline product obtained from the eluate withtoluene/ethyl acetate (3/1-1/1 v/v) was recrystallized from ether,whereby 1.91 g (64.7%) of the objective compound (I a-38) melting at62.5°-63.5° C. was obtained.

EXAMPLE 40

The reaction was carried out in the same method as mentioned above. Thereaction conditions are shown in Table 4 and properties of the objectivecompounds are shown in Table 5.

                                      TABLE 4                                     __________________________________________________________________________     ##STR51##                                                                                               Reaction                                              Compound                Conditions                                                                           Compound (I a)                                                                        Com-                                Ex.                                                                              (II)  Compound (IV)     Temp. (°C.)                                                                   Yield   pound                               No.                                                                              g (mmol)                                                                            R            g (mmol)                                                                           Time   (g) (%) No.                                 __________________________________________________________________________    40  4.8 (23.4)                                                                          ##STR52##    5.3* (19.5)                                                                       115-120 3 hr.                                                                        3.51                                                                              62.8                                                                              I a-39                              __________________________________________________________________________     *phthalimidate                                                           

EXAMPLE 411-[N-Methyl-[2-(4-methoxyphenyl)aminoethyl]carbamoyl]-2-oxopyrrolidine(I a-40) ##STR53##

A mixture of 5.31 g (25.9 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine(II) and 4.67 g (25.9 mmol) of Compound (IV) was heated with stirring at110°-120° C. for 4 hr. in a bath. After cooling, the reaction solutionwas refined by silica gel column chromatography, whereby 5.57 g of theoily objective compound (I a-40) was obtained from the eluate withtoluene/ethyl acetate (1/1 v/v) and ethyl acetate, respectively. Yield:74.0%.

The properties of the objective compound are shown in Table 5.

EXAMPLE 421-[N-Methyl[2-(4-methoxyphenyloxy)ethyl]carbamoyl]-2-oxopyrrolidine (Ia-41) ##STR54##

A mixture of 1.87 g (9.13 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine(II), 2.39 g (9.13 mmol) of 2-(4-methoxyphenyloxy)ethyl-N-methylaminehydrobromide and 2.30 g (22.8 mmol) of triethylamine in 0.5 ml of DMAwas heated at 115°-125° C. for 6.5 hr. and ethyl acetate was added tothe reaction solution. The mixture was washed with aqueous NaHCO₃ andwater, and dried, then the solvent was distilled off. The residue wasrefined by silica gel column chromatography, whereby 2.37 g of an oilycompound (I a-41) was obtained from the eluate with toluene/ethylacetate (5/1-3/1 v/v). Yield: 88.8%

The properties of the objective compound are shown in Table 5.

EXAMPLE 43 1-[[2-(4-Methoxyphenyloxy)ethyl]carbamoyl]-2-oxopyrrolidine(I a-42) ##STR55##

A mixture of 1.16 g (5.64 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine(II) were added 2.0 g (8.06 mmol) of 2-(4-methoxyphenyloxy)ethylaminehydrobromide and 1.63 g (16.1 mmol) of triethylamine was heated at 110°C. for 3 hr. After evaporation of the solvent, the residue was refinedby silica gel column chromatography, whereby 1.86 g of the objectivecompound (I a-42) was obtained as crystals from the eluate withtoluene/ethyl acetate (5/1-3/1 v/v). Yield: 83.0%

The objective compound melting at 62.5°-64.5° C. was obtained byrecrystallizing from ethanol-ether. The properties of the objectivecompound (I a-42) are shown in Table 5.

EXAMPLE 441-[N-Ethyl-[2-(4-methoxyphenyl)(n-propyl)amino]ethyl]carbamoyl]-2-oxopyrrolidine(I a-43) ##STR56##

To a mixture of 1.01 g (3.16 mmol) of1-[2-[(4-methoxyphenyl)(n-propyl)amino]ethyl]carbamoyl]-2-oxopyrrolidine(I a-4) in 15 ml of THF was added 126 mg (3.16 mmol) of NaH (60%) atroom temperature, and the mixture was stirred for 50 min. Then, themixture was added to 0.265 ml (3.32 mmol) of EtI and stirred for 3 daysat room temperature. The reaction solution was mixed with ethyl acetateand dried, and the solvent was removed by evaporation. The oily residueobtained was refined by silica gel column chromatography, whereby 330 mgof an oily compound (I a-43) was obtained from the eluate withtoluene/ethyl acetate (3/1-1/1 v/v).

Yield: 30%.

The properties of the objective compound are shown in Table 5.

                                      TABLE 5                                     __________________________________________________________________________         m.p. (°C.)                                                        Compd.                                                                             (Recrystalli-                                                                        Elementary Analysis                                                                       IR (cm.sup.-1)                                        No.  zing Solvent)                                                                        Found (Calcd.) (%)                                                                        (CHCl.sub.3)                                                                          NMR (CDCl.sub.3) δ                      __________________________________________________________________________    Ia-36                                                                              102.0-103.0                                                                          C.sub.14 H.sub.19 N.sub.3 O.sub.2                                                         3280, 1705, 1670                                                                      2.00 (quint, J=7Hz, 2H), 2.21 (s, 3H),                                        2.57                                               (EtOH) C, 64.41 (64.32)                                                                          1610, 1535, 1510                                                                      (t, J=7Hz, 2H), 3.20-3.60 (m, 4H), 3.83                                       (t,                                                       H,  7.33  (7.33)    J=7hz, 2H), 6.53, 6.96 (A.sub.2 B.sub.2,                                      J=9Hz, 4H),                                               N, 16.05 (16.08)    8.57 (br., 1H)                                Ia-37                                                                              141.0-142.0                                                                          C.sub.13 H.sub.16 N.sub.3 O.sub.2 Cl                                                      3280, 1705, 1670                                                                      (CDCl.sub.3 /CD.sub.3 OD = 3/1)                    (EtOH) C, 55.35 (55.42)                                                                          1595, 1530, 1495                                                                      2.04 (quint, J=7Hz, 2H), 2.61 (t, J=7Hz,                                      2H)                                                       H,  5.62  (5.72)    3.21-3.65 (m, 4H), 3.86 (t, J=7Hz, 2H),                                       6.57                                                      N, 14.95 (14.91)    7.13 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.70                                       (br., 1H)                                                 Cl, 12.47 (12.58)                                                 Ia-38                                                                              98.5-99.5                                                                            C.sub.11 H.sub.16 N.sub.4 O.sub.3                                                         3300, 1710, 1680                                                                      2.02 (quint, J=7Hz, 2H), 2.27 (s, 3H),                                        2.59                                               (EtOH) C, 52.34 (52.37)                                                                          1630, 1540                                                                            (t, J=7Hz, 2H), 3.30-3.55 (m, 4H), 3.83                                       (t,                                                       H,  6.38  (6.39)    J=7Hz, 2H), 5.47 (s, 1H), 8.60 (br., 1H)                  N, 22.24 (22.21)                                                  Ia-39                                                                              62.5-63.5                                                                            C.sub.10 H.sub.14 N.sub.4 O.sub.2                                                         3280, 1700,                                                                           1.83-2.17 (m, 2H), 2.57 (t, J=7Hz, 2H),                                       3.75                                               (Et.sub.2 O)                                                                         C, 54.21 (54.04)                                                                          1670 (sh), 1530                                                                       (q, J=5Hz, 2H), 3.83 (t, J=7Hz, 2H),                                          4.28                                                      H,  6.38  (6.35)    (t, J=5Hz, 2H), 6.23 (d, J=2H, 1H), 7.37                                      (d,                                                       N, 25.26 (25.21)    J=2Hz, 1H), 7.53 (d, J=2Hz, 1H), 8.53                                         (br.,                                                                         1H)                                           Ia-40                                                                              --     C.sub.15 H.sub.21 N.sub.3 O.sub.3                                                         1710, 1660, 1500                                                                      1.92 (quint, J=7Hz, 2H), 2.40 (t, J=7Hz,                                      2H)                                                       C, 61.61 (61.84)                                                                          1470 (sh), 1455                                                                       2.99 (s, 3H), 3.26 (t, J=6Hz, 2H),                                            3.50-3.80                                                 H,  7.22  (7.27)    (m, 4H), 3.72 (s, 3H), 6.57, 6.76                                             (A.sub.2 B.sub.2, J=                                      N, 14.09 (14.42)    9Hz, 4H)                                      Ia-41                                                                              --     C.sub.15 H.sub.20 N.sub.2 O.sub.4                                                         1710, 1660, 1495                                                                      2.00 (quint, J=7Hz, 2H), 2.42 (t, J=7Hz,                                      2H)                                                       C, 61.60 (61.63)                                                                          1470 (sh), 1455                                                                       3.10 (s, 3H), 3.75 (s, 3H), 3.60-3.80                                         (m,                                                       H,  6.97  (6.90)                                                                          1440 (sh), 1420                                                                       4H), 4.10 (t, J=6Hz, 2H), 6.83 (s, 4H)                    N,  9.50  (9.58)                                                                          (sh)                                                  Ia-42                                                                              62.5-64.5                                                                            C.sub.14 H.sub.18 N.sub.2 O.sub.4                                                         3280, 1705,                                                                           1.98 (quint, J=7Hz, 2H), 2.55 (t, J=7Hz,                                      2H)                                                (EtOH-Et.sub.2 O)                                                                    C, 60.45 (60.42)                                                                          1670 (sh), 1530,                                                                      3.75 (s, 3H), 3.52-4.06 (m, 6H)                           H,  6.55  (6.52)                                                                          1505, 1460                                                        N, 10.01 (10.07)                                                  Ia-43                                                                              --     C.sub.19 H.sub.29 N.sub.3 O.sub.3                                                         1705, 1650, 1500                                                                      0.88 (t, J=7Hz, 3H), 1.18 (t, J=7Hz,                                          3H),                                                      C, 65.45 (65.68)                                                                          1450, 1415                                                                            1.33-2.00 (m, 4H), 2.30 (t, J=7Hz, 2H),                   H,  8.49  (8.41)    3.00-3.55 (m, 10H), 3.74 (s, 3H), 6.65,                   N, 11.95 (12.10)    6.79 (A.sub.2 B.sub.2, J=9Hz,                 __________________________________________________________________________                                    4H)                                       

EXAMPLE 451-[2-[(4-Methoxyphenyl)allylamino]ethyl]carbamoyl-2-oxopyrrolidine (Ia-44) ##STR57##

To a solution of 2.20 g (7.93 mmol) of1-[2-[(4-methoxyphenylamino)ethyl]carbamoyl]-2-oxopyrrolidine (I a-1) in10 ml of DMA were added 1.01 ml (11.9 mmol) of allyl bromide and 1.92 ml(23.8 mmol) of pyridine, and the mixture was stirred for 20 min. at80°-85° C. To the mixture were added 1.5 ml of pyridine and 0.8 ml ofallyl bromide, and the mixture was further stirred for 10 min. and 1 hr.at the same temperature. The reaction solution was poured into ethylacetate and washed with aqueous NaHCO₃, water, and saturated brine inorder. After drying, the solvent was removed by evaporation. The residuewas refined by silica gel column chromatography, and the resultingcrystalline compound from the eluate with toluene/ethyl acetate (8/1-3/1v/v) was recrystallized from ether-n-hexane, whereby 1.92 g of theobjective compound (I a-44) melting at 53.0°-54.0° C. was obtained ascrystals. Yield: 76.4%.

Anal. Calcd. (%) for C₁₇ H₂₃ N₃ O₃ : C, 64.33; H, 7.30; N, 13.24. Found(%): C, 64.13; H, 7.35; N, 13.35.

IR (CHCl₃): 3310, 1705, 1675, 1540, 1505 cm⁻¹.

NMR (CDCl₃): 1.83-2.17 (m, 2H), 2.57 (t, J=7 Hz, 2H) 3.40 (s, 4H), 3.73(s, 3H), 3.80-3.90 (m, 4H), 5.05-5.25 (m, 2H), 5.60-6.05 (m, 1H), 6.80(s, 4H), 8.52 (br., 1H).

EXAMPLE 46 1-[[2-(4-Methoxyphenylthio)ethyl]carbamoyl]-2-oxopyrrolidine(I a-45) ##STR58##

To a solution of 2.10 g (11.0 mmol) of1-[2-chloroethylcarbamoyl]-2-oxopyrrolidine and 1.40 g (10 mmol) of4-methoxybenzenethiol in 25 ml of DMF were added 2.47 g (16.5 mmol) ofNaI and 3.02 g (22 mmol) of K₂ CO₃, and the mixture was heated at 100°C. for 4.5 hr. The reaction solution was poured into ethyl acetate,washed with water, diluted hydrochloric acid, water, and saturated brinein order. After drying, the solvent was removed by evaporation. Theresidue was refined by silica gel column chromatography, whereby 2.78 g(94.6%) of the crystalline objective compound (I a-45) was obtained fromthe eluate with benzene/ethyl acetate (8/1-5/1 v/v). The needles meltingat 64.0°-65.0° C. are obtained by recrystallizing from ether-n-hexane.The properties of the objective compound (I a-45) are shown in Table 7.

EXAMPLES 47-52

The reactions were carried out in the same method as in Example 46. Thereaction conditions are shown in Table 6 and the properties are in Table7.

                                      TABLE 6                                     __________________________________________________________________________     ##STR59##                                                                    Compound                          Reaction                                    (III-1) HSR           K.sub.2 CO.sub.3                                                                  NaI     Conditions                                                                           Compound (Ia)                        Ex.                                                                             g               g   g   g   DMF Temp. (°C.)                                                                   Yield                                No.                                                                             (mmol)                                                                              R         (mmol)                                                                            (mmol)                                                                            (mmol)                                                                            (ml)                                                                              Time   (g)                                                                              (%)                                                                              No.                            __________________________________________________________________________    47                                                                              3.50 (18.4)                                                                          ##STR60##                                                                              2.15 (19.3)                                                                       5.05 (36.8)                                                                       4.14 (27.6)                                                                       40  110 21 hr.                                                                           2.83                                                                             58.0                                                                             Ia-46                          48                                                                              2.50 (13.1)                                                                          ##STR61##                                                                              1.54 (13.8)                                                                       3.6 (26.2)                                                                        2.94 (19.6)                                                                       25  100-105 89 hr.                                                                       2.60                                                                             74.4                                                                             Ia-47                          49                                                                              2.50 (13.1)                                                                          ##STR62##                                                                              1.40 (13.8)                                                                       3.6 (26.2)                                                                        2.94 (19.6)                                                                       25  105 89.5 hr.                                                                         0.85                                                                             25.4                                                                             Ia-48                          50                                                                              1.09 (5.25)                                                                          ##STR63##                                                                              0.73 (5.51)                                                                       1.44 (10.5)                                                                       1.18 (7.88)                                                                       20  110 3 hr.                                                                            0.57                                                                             45.9                                                                             Ia-49                          51                                                                              3.50 (18.4)                                                                          ##STR64##                                                                              2.30 (19.3)                                                                       5.05 (36.8)                                                                       4.14 (27.6)                                                                       40  110 14 hr.                                                                           2.37                                                                             47.2                                                                             Ia-50                          52                                                                              3.50 (18.4)                                                                          ##STR65##                                                                              3.70 (22.1)                                                                       5.05 (36.8)                                                                       4.14 (27.6)                                                                       40  110 14 hr.                                                                           5.02                                                                             85.0                                                                             Ia-51                          __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________         m.p. (°C.)                                                        Compd.                                                                             (Recrystalli-                                                                        Elementary Analysis                                                                      IR                                                     No.  zing solvent)                                                                        Found (Calcd.) (%)                                                                       (CHCl.sub.3)                                                                          NMR (CDCl.sub.3) δ                       __________________________________________________________________________    Ia-45                                                                              64.0-65.0                                                                            C.sub.14 H.sub.18 N.sub.2 O.sub.3 S                                                      3290, 1700, 1670                                                                      1.80-2.16 (m, 2H), 2.57 (t, J=7Hz, 2H),             (Et.sub.2 O-                                                                         C, 57.12 (57.12)                                                                         1585, 1530, 1485                                                                      2.97 (t, J=7Hz, 2H), 3.45 (q, 7Hz, 2H),             n-hexane)                                                                            H, 6.03 (6.16)                                                                           1450, 1430                                                                            3.80 (s, 3H), 3.82 (t, J=7Hz, 2H), 6.85,                   N, 9.53 (9.52)     7.40 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.67                                       (br., 1H)                                                  S, 10.90 (10.89)                                                  Ia-46                                                                              62.5-63.5                                                                            C.sub.12 H.sub.15 N.sub.3 O.sub.2 S                                                      3300, 1700, 1675                                                                      1.83-2.18 (m, 2H), 2.57 (t, J=7Hz, 2H),             (Et.sub.2 O)                                                                         C, 54.39 (54.32)                                                                         1575, 1530, 1485                                                                      3.25-3.66 (m, 4H), 3.83 (t, J=7Hz, 2H),                    H, 5.70 (5.70)                                                                           1450, 1405                                                                            6.85-7.60 (m, 3H), 8.45 (dd, J.sub.1                                          =6Hz,                                                      N, 15.83 (15.84)   J.sub.2 =2Hz), 8.67 (br., 1H)                              S, 11.96 (12.08)                                                  Ia-47                                                                              96.0-97.0                                                                            C.sub.11 H.sub.14 N.sub.4 O.sub.2 S                                                      3300, 1700, 1670                                                                      1.83-2.20 (m, 2H), 2.58 (t, J=7Hz, 2H),             (EtOH) C, 49.60 (49.61)                                                                         1550 (sh), 1540                                                                       3.33 (t, J=7Hz, 2H), 3.62 (q, J=7Hz, 2H),                  H, 5.33 (5.30)     3.84 (t, J=7Hz, 2H), 6.97 (t, J=5Hz, 1H),                  N, 20.97 (21.04)   8.55 (d, J=5Hz, 2H), 8.70 (br., 1H)                        S, 11.94 (12.04)                                                  Ia-48                                                                              123.0-124.0                                                                          C.sub.9 H.sub.13 N.sub.5 O.sub.2 S                                                       3375, 3270, 1710                                                                      (CDCl.sub.3.CDOD=3/1)                               (EtOH) C, 42.32 (42.24)                                                                         1675    1.86-2.20 (m, 2H), 2.62 (t, J=7H, 2H),                     H, 5.13 (5.13)     3.27 (t, J=7Hz, 2H), 3.60 (q, J=7Hz, 2H),                  N, 27.27 (27.43)   3.83 (t, J=7Hz, 2H), 8.13 (s, 1H), 8.77                    S, 12.46 (12.56)   (br. s, 1H)                                    Ia-49                                                                              112.0-113.0                                                                          C.sub.10 H.sub.14 N.sub.4 O.sub.2 S.sub.2                                                3300, 1705, 1675                                                                      1.87-2.20 (m, 2H), 2.59 (t, J=7Hz, 2H),                                       2.71                                                (EtOH) C, 41.98 (41.94)                                                                         1530, 1480, 1450                                                                      (s, 3H), 3.40-3.95 (m, 6H), 8.70 (br.,                                        1H)                                                        H, 4.96 (4.93)                                                                           1425, 1375                                                         N, 19.62 (19.56)                                                              S, 22.36 (22.39)                                                  Ia-50                                                                              71.0-72.0                                                                            C.sub.10 H.sub.15 N.sub.3 O.sub.2 S.sub.2                                                3300, 1705, 1680                                                                      1.85-2.20 (m, 2H), 2.60 (t, J=7Hz, 2H),             (EtOH) C, 44.05 (43.94)                                                                         1560 (sh), 1530                                                                       3.19-3.47 (m, 4H), 3.57 (t, J=7Hz, 2H),                                       3.83                                                       H, 5.51 (5.53)                                                                           1480, 1455, 1430                                                                      (t, J=7Hz, 2H), 4.20 (t, J=7Hz, 2H), 8.63                  N, 15.40 (15.37)   (br., 1H)                                                  S, 23.40 (23.46)                                                  Ia-51                                                                              114.5-115.5                                                                          C.sub.14 H.sub.15 N.sub.3 O.sub.2 S.sub.2                                                3300, 1700, 1680                                                                      1.77-2.10 (m, 2H), 2.48 (t, J=7Hz, 2H),             (EtOH) C, 52.27 (52.32)                                                                         1530, 1480, 1455                                                                      3.45-3.78 (m, 4H), 3.80 (t, J=7Hz, 2H),                    H, 4.52 (4.70)                                                                           1420    7.15-7.50 (m, 2H), 7.67-7.90 (m, 2H),                                         8.70                                                       N, 12.88 (13.70)   (br., 1H)                                                  S, 20.10 (19.95)                                                  __________________________________________________________________________

EXAMPLE 531-[[2-(4-Methoxybenzenesulfonyl)ethyl]carbamoyl]-2-oxopyrrolidine (Ib-1) ##STR66##

To a solution of 0.70 g (2.38 mmol) of1-[[2-(4-methoxyphenylthio)ethyl]carbamoyl]-2-oxopyrrolidine in 30 ml ofCH₂ Cl₂ was added 0.96 g (4.76 mmol) of m-CPBA (content 85%), and themixture was stirred for 1.5 hr. at room temperature. The reactionsolution was poured into ethyl acetate, washed with aqueous NaHCO₃ andwater. After drying, the solvent was removed by evaporation. The residuewas refined by silica gel column chromatography, then the crystallineobjective compound was obtained from the eluate with benzene/ethylacetate (1/1 v/v). The product was recrystallized from ether to give0.684 g of crystals (I b-1) melting at 124.0°-125.0° C.

Yield: 88.0%.

The properties of the objective compound are shown in Table 10.

EXAMPLE 54

The reaction was carried out in the same method as in Example 53. Thereaction conditions are shown in Table 8 and the properties are in Table10.

                                      TABLE 8                                     __________________________________________________________________________     ##STR67##                                                                                            Reaction                                              Compound (I a)     m-CPBA                                                                             Conditions                                                                           Compound (I b)                                 Ex.       mg  CH.sub.2 Cl.sub.2                                                                  g    Temp. (°C.)                                                                   Yield   Compound                               No.                                                                              R      (mmol)                                                                            (ml) (mmol)                                                                             Time   (g) (%) No.                                    __________________________________________________________________________    54                                                                                ##STR68##                                                                            1.66 (6.23)                                                                      55    2.70* (12.5)                                                                      Room Temp. 3 hr.                                                                     1.10                                                                              59.1                                                                              I b-2                                  __________________________________________________________________________     *Content 80%                                                             

EXAMPLE 55 2-Oxo-1-[[2-(pyridin-2-ylsulfinyl)ethyl]carbamoyl]pyrrolidine(I b-3)

To a solution of 2.0 g (7.54 mmol) of2-oxo-1-[[2-(pyridin-2-ylthio)ethyl]carbamoyl]pyrrolidine in 35 ml ofCH₂ Cl₂ was added 1.63 g (7.54 mmol) of m-CPBA (content 80%) underice-cooling. Then the mixture was stirred for 1.5 hr. at roomtemperature. The reaction solution was washed with aqueous NaHCO₃ andwater. After drying, the solvent was removed by evaporation. The residuewas refined by silica gel column chromatography, then the crystallineobjective compound was obtained from the eluate with benzene/ethylacetate (3/1-1/1 v/v). The compound was washed with Et₂ O and collectedby filtration, whereby 0.93 g of the crystalline compound (I b-3)melting at 119.5°-120.5° C. was obtained. Yield: 43.9%.

The properties of the objective compounds are shown in Table 8.

EXAMPLE 56-57

In the same method as in Example 55, the reactions were carried out asshown in Table 9. The properties are shown in Table 10.

                                      TABLE 9                                     __________________________________________________________________________     ##STR69##                                                                                               Reaction                                           Compound (I a)        m-CPBA                                                                             Conditions                                                                           Compound (I b)                              Ex.          mg  CH.sub.2 Cl.sub.2                                                                  g    Temp. (°C.)                                                                   Yield   Compound                            No.                                                                              R         (mmol)                                                                            (ml) (mmol)                                                                             Time   (g) (%) No.                                 __________________________________________________________________________    56                                                                                ##STR70##                                                                               1.62 (6.08)                                                                      45    1.23* (6.08)                                                                      Room Temp. 2.25 hr.                                                                  1.08                                                                              62.9                                                                              I b-4                               57                                                                                ##STR71##                                                                                2.13 (6.62)                                                                     30    1.43** (6.62)                                                                     Room Temp. 2.5 hr.                                                                   1.86                                                                              83.2                                                                              I b-5                               __________________________________________________________________________     *Content 85%;                                                                 **Content 80%                                                            

                                      TABLE 10                                    __________________________________________________________________________         m.p. (°C.)                                                        Compd.                                                                             (Recrystalli-                                                                        Elementary Analysis                                                                       IR (cm.sup.-1)                                        No.  zing solvent)                                                                        Found (Calcd.) (%)                                                                        (CHCl.sub.3)                                                                          NMR (CDCl.sub.3) δ                      __________________________________________________________________________    Ib-1 124.0-125.0                                                                          C.sub.14 H.sub.18 N.sub.2 O.sub.5 S                                                       3300, 1710, 1685                                                                      1.80-2.15 (m, 2H), 2.56 (t, J=7Hz, 2H),                                       3.37                                               (EtOH) C, 51.48 (51.52)                                                                          1595, 1580, 1535                                                                      (t, J=6Hz, 2H), 3.62 (q, J=6Hz, 2H),                                          3.74                                                      H,  5.52  (5.56)                                                                          1500    (t, J=7Hz, 2H), 3.88 (s, 3H), 7.02, 7.84                  N,  8.64  (8.58)    (A.sub.2 B.sub.2, J=9Hz, 4H), 8.64 (br.                                       s, 1H)                                                    S,  9.87  (9.82)                                                  Ib-2 104.5-105.5                                                                          C.sub.11 H.sub.14 N.sub.4 O.sub.4 S                                                       3300, 1710, 1685                                                                      1.85-2.18 (m, 2H), 2.57 (t, J=7Hz, 2H),            (EtOH) C, 44.25 (44.29)                                                                          1560, 1535, 1485                                                                      3.73-3.90 (m, 6H), 7.58 (t, J=5Hz, 1H),                   H,  4.70  (4.73)                                                                          1460, 1430                                                                            8.98 (d, J=5Hz, 2H), 8.74 (br., 1H)                       N, 18.74 (18.78)                                                              S, 10.63 (10.75)                                                  Ib-3 119.5-120.5                                                                          C.sub.12 H.sub.15 N.sub.3 O.sub.3 S                                                       3290, 1710, 1680                                                                      1.80-2.16 (m, 2H), 2.56 (t, J=7Hz, 2H),            (Et.sub.2 O)                                                                         C, 51.18 (51.23)                                                                          1575, 1530                                                                            3.02-3.41 (m, 2H), 3.55-3.87 (m, 4H),                     H,  5.26  (5.37)    7.27-7.45 (m, 1H), 7.80-8.07 (m, 2H),                     N, 14.87 (14.94)    8.50-8.75 (m, 2H)                                         S, 11.47 (11.40)                                                  Ib-4 123.0-124.0                                                                          C.sub.11 H.sub.14 N.sub.4 O.sub.3 S                                                       3290, 1710, 1685                                                                      1.84-2.19 (m, 2H), 2.57 (t, J=7Hz, 2H),            (EtOH) C, 46.83 (46.80)                                                                          1560, 1530                                                                            3.23-3.50 (m, 2H), 3.66-3.88 (m, 4H),                                         7.43                                                      H,  5.06  (5.00)    (t, J=6Hz, 1H), 8.57 (br., 1H), 8.90 (d,                  N, 19.71 (19.85)    J=6Hz, 2H)                                                S, 11.08 (11.36)                                                  Ib-5 144.0-145.0                                                                          C.sub.14 H.sub.15 N.sub.3 O.sub.3 S.sub.2                                                 3280, 1710, 1685                                                                      1.70-2.00 (m, 2H), 2.27-2.50 (m, 2H),                                         3.50-                                              (EtOH) C, 49.86 (49.84)                                                                          1525    3.95 (m, 6H), 7.37-7.66 (m, 2H),                                              7.95-8.14                                                 H,  4.35  (4.48)    (m, 2H), 8.53 (br., 1H)                                   N, 12.39 (12.45)                                                              S, 18.87 (19.00)                                                  __________________________________________________________________________

EXAMPLES 58-65

The reactions were carried out in the same method as in theaforementioned Example 1, whereby the compounds (I a) were obtained. Thereaction conditions and the properties of the objective compounds areshown in Tables 11 and 12, respectively.

                                      TABLE 11                                    __________________________________________________________________________     ##STR72##                                                                    Compound                 Reaction                                             (III-2)  (V) K.sub.2 CO.sub.3                                                                  NaI     Condition                                                                            Compound (Ia)                                 Ex.                                                                              g     g   g   g   DMF Temp. (°C.)   Yield Compd.                    No.                                                                              (mmol)                                                                              (mmol)                                                                            (mmol)                                                                            (mmol)                                                                            (ml)                                                                              Time   Z.sup.1,Z.sup.2                                                                             (g)                                                                              (%)                                                                              No.                       __________________________________________________________________________    58 3.17 (15.5)                                                                         2.10 (17.0)                                                                       5.36 (38.8)                                                                       3.48 (23.2)                                                                       35  105-110 29 hr.                                                                        ##STR73##    1.90                                                                             42.1                                                                             Ia-52                     59 3.00 (14.7)                                                                         3.41 (16.1)                                                                       5.08 (36.8)                                                                       3.30 (22.1)                                                                       35  100-105 6 d.                                                                          ##STR74##    4.24                                                                             76.0                                                                             Ia-53                     60 3.00 (14.7)                                                                         2.84 (16.1)                                                                       5.08 (36.8)                                                                       3.30 (22.1)                                                                       35  100-105 6 d.                                                                          ##STR75##    4.29                                                                             85.0                                                                             Ia-54                     61 2.74 (13.4)                                                                         2.50 (14.1)                                                                       4.63 (33.5)                                                                       3.0 (20.1)                                                                        30  100-105 3 d.                                                                          ##STR76##    3.95                                                                             85.4                                                                             Ia-55                     62 1.23 (6.0)                                                                          1.27 (6.12)                                                                       2.07 (15.0)                                                                       1.35 (9.0)                                                                        20   95-100 4 d.                                                                          ##STR77##    1.49                                                                             66.0                                                                             Ia-56                     63 3.73 (18.2)                                                                          3.34 (18.2)                                                                      7.55 (54.6)                                                                       4.06 (27.3)                                                                       35  100-105 4 d.                                                                          ##STR78##    5.76                                                                             89.9                                                                             Ia-57                     64 2.08 (10.9)                                                                         2.14 (11.6)                                                                       4.52 (32.7)                                                                       2.45 (16.4)                                                                       30  100-105 4 d.                                                                          ##STR79##    3.12                                                                             81.5                                                                             Ia-58                     65 2.99 (14.6)                                                                         3.10 (14.6)                                                                       6.05 (43.8)                                                                       3.28 (21.9)                                                                       35  100-105 5 d.                                                                          ##STR80##    4.96                                                                             89.3                                                                             Ia-59                     __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________          m.p. (°C.)                                                       Compound                                                                            (Recrystalli-                                                                         Elementary Analysis                                             No.   zing solvent)                                                                         Found (Calcd.) (%)                                                                        IR (cm.sup.-1)                                                                        NMR (CDCl.sub.3) δ                    __________________________________________________________________________    Ia-52 114.5-115.5                                                                           C.sub.15 H.sub.21 N.sub.3 O.sub.3                                                         (CHCl.sub.3)                                                                          1.83 (t, J=6Hz, 2H), 2.01 (quint,                                             J=7Hz, 2H)                                        (EtOH)  C, 61.78 (61.84)                                                                          3280, 1700, 1670                                                                      2.60 (t, J=7Hz, 2H), 3.16 (t, J=6Hz,                                          2H),                                                      H,  7.13  (7.26)                                                                          1540, 1500, 1480                                                                      3.45 (q, J=6Hz, 2H), 3.75 (s, 3H), 3.86                                       (t,                                                       N, 14.36 (14.42)                                                                          1455    J=7Hz, 2H), 6.60, 6.80 (A.sub.2                                               B.sub.2, J=9Hz, 4H),                                                          8.50 (br., 1H)                              Ia-53 138.0-139.0                                                                           C.sub.19 H.sub.26 N.sub.3 O.sub.3 Cl                                                      (CHCl.sub.3)                                                                          1.60-3.40 (m, 16H), 3.36 (q, J=6Hz,                                           2H),                                              (EtOH-Et.sub. 2 O)                                                                    C, 59.73 (60.07)                                                                          3290, 1700, 1670                                                                      3.77 (t, J=7Hz, 2H), 7.30, 7.47                                               (A.sub.2 B.sub.2, J=9Hz                                   H,  6.92  (6.90)                                                                          1535, 1480                                                                            4H), 8.58 (br., 1H)                                       N, 10.93 (11.06)                                                              Cl, 9.55  (9.33)                                                Ia-54 dimaleate                                                                             C.sub.19 H.sub.28 N.sub.4 O.sub.2.                                                        (Nujol) (CD.sub.3 OD: D.sub.2 O=6:1)                      200.0-201.0                                                                           2C.sub.4 H.sub.4 O.sub.4                                                                  dimaleate                                                                             dimaleate                                         (d)     C, 56.02 (56.24)                                                                          3250, 1700                                                                            1.78-2.03 (m, 4H), 2.54 (t, J=7Hz,                                            2H),                                              (MeOH-  H,  6.28  (6.29)                                                                          1680 (sh), 1610                                                                       3.03-3.93 (m, 12H), 3.68 (t, J=7Hz,                                           2H),                                              i-PrOH) N,  9.75  (9.72)                                                                          1560    4.19 (s, 2H), 6.21 (s, 4H), 7.42 (s,                                          5H)                                         Ia-55 94.5-95.5                                                                             C.sub.19 H.sub.27 N.sub.3 O.sub.3                                                         (CHCl.sub.3)                                                                          1.70-2.88 (m, 17H), 3.37 (q, J=6Hz,                                           2H)                                               (i-PrOH-                                                                              C, 66.13 (66.06)                                                                          3295, 2920, 2800                                                                      3.85 (t, J=7Hz, 2H), 7.20-7.60 (m, 5H),                                       8.57                                              Et.sub.2 O)                                                                           H,  7.84  (7.88)                                                                          1705, 1670, 1535                                                                      (br., 1H)                                                 N, 12.14 (12.17)                                                Ia-56 98.5-99.0                                                                             C.sub.20 H.sub.29 N.sub.3 O.sub.4                                                         (CHCl.sub.3)                                                                          1.60-2.90 (m, 17H), 3.36 (q, J=6Hz.                                           2H)                                               (i-PrOH-                                                                              C, 63.69 (63.97)                                                                          3275, 2920, 1705                                                                      3.79 (s, 3H), 3.83 (t, J=7Hz, 2H),                                            6.86,                                             Et.sub.2 O)                                                                           H,  7.83   (7.79)                                                                         1603, 1535, 1505                                                                      7.44 (A.sub.2 B.sub.2, J=9Hz, 4H), 8.55                                       (br., 1H)                                                 N, 11.20 (11.19)                                                Ia-57 1/2(COOH).sub.2                                                                       C.sub.17 H.sub.25 N.sub.3 O.sub.3 S.CHO.sub.2                                             (Nujol) (free base)                                       224.0-226.0                                                                           C, 54.42 (54.81)                                                                          1/2(COOH).sub.2                                                                       1.744 (quint, J=7.2Hz, 17H), 1.85-2.25                                        (m,                                               (d)     H,  6.51  (6.64)                                                                          3290, 3110, 1700                                                                      6H), 2.40-2.80 (m, 8H), 3.346 (q,                                             J=6Hz,                                            (MeOH-  N, 10.56 (10.65)                                                                          1678, 1630                                                                            2H), 3.83 (t, J=7Hz, 2H), 6.97-6.98 (m,                                       2H),                                              i-PrOH) S,  7.93  (8.13)    7.17-7.21 (m, 1H), 8.516 (br., 1H)          Ia-58 (COOH).sub.2                                                                          C.sub.17 H.sub.25 N.sub.3 O.sub.3 S.                                                      (Nujol) (free base)                                       144.0-145.0                                                                           C.sub.2 H.sub.2 O.sub.4 1/2H.sub.2 O                                                      (COOH).sub.2                                                                          1.65-1.85 (m, 4H), 1.90-2.10 (m, 5H),                                         2.240,                                            (i-PrOH)                                                                              C, 50.86 (50.66)                                                                          3450, 3310, 3230                                                                      2.879 (ABq, J=11Hz, 2H), 2.469 (t,                                            J=7Hz,                                                    H,  6.08  (6.26)                                                                          1700, 1665, 1640                                                                      2H), 2.613 (t, J=8Hz, 2H), 2.937 (br.,                    N,  9.26  (9.33)                                                                          1620 (sh)                                                                             J=12Hz, 1H), 3.900 (m, 2H), 3.865 (t,                                         J=7Hz,                                                    S,  7.12  (7.12)    2H), 4.230 (br. s, 1H), 6.956-6.974                                           (m,                                                                           2H), 7.187-7.273 (m, 1H), 8.607 (br. s,                                       1H)                                         Ia-59 74.5-76.0                                                                             C.sub.19 H.sub.26 N.sub.3 O.sub.3 Cl                                                      (CHCl.sub.3)                                                                          1.65-1.82 (m, 5H), 190-2.10 (m, 4H),                                          2.198                                             (Et.sub.2 O)                                                                          C, 60.16 (60.07)                                                                          3470, 3300, 1705                                                                      (a part of ABq, J=11Hz, 1H), 2.467 (t,                    H,  6.72  (6.90)                                                                          1670, 1540, 1485                                                                      J=5Hz, 2H), 4.16 (s, 1H), 7.26-7.50 (m,                                       4H),                                                      N, 11.12 (11.06)    8.594 (br. s, 1H)                                         S,  9.40  (9.33)                                                __________________________________________________________________________

EXAMPLE 661-[[3-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)propyl]carbamoyl]-2-oxopyrrolidinemaleate (I c-1) ##STR81##

A solution of 1.67 g (4.83 mmol) of1-[[3-(4-hydroxy-4-phenyl-1-piperidino)propyl]carbamoyl]-2-oxopyrrolidine(I a-55) in 25 ml of 10% hydrochloric acid was refluxed for 2 hr. Thereaction solution was made alkaline with aqueous NaHCO₃, extracted withethyl acetate, and washed with saturated brine. After drying, thesolvent was removed by evaporation. The residue was refined by silicagel column chromatography, whereby 0.65 g of the objective product (Ic-1) was obtained from the eluate with ethyl acetate. Yield: 41%

The objective product (I c-1) (maleate) was recrystallized fromisopropyl alcohol-ether, whereby crystals melting at 145.0°-148° C. wereobtained.

The properties of the objective compound (I c-1) are shown in Table 13.

EXAMPLE 671-[[3-[4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine(I c-2) ##STR82##

A solution of 1.6 g (4.21 mmol) of1-[[3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine(I a-53) and 0.96 g (5.05 mmol) of p-toluenesulfonic acid monohydrate in75 ml of toluene was refluxed for 29 hr. The water was removedazeotropically using a Dean-Stark trap containing 10 g of MolecularSieves-4A. The solution, after being made alkaline with aqueous NaOH,was extracted with ethyl acetate, and the organic layer was washed withwater and saturated brine in order. After drying, the solvent wasremoved by evaporation. The residue was refined by silica gel columnchromatography, whereby 1.50 g of the objective crystalline compound (Ic-2) was obtained from the eluate with ethyl acetate and then CH₂ Cl₂/MeOH (20/1 v/v).

Yield: 98.4%.

By recrystallizing from ether-isopropyl alcohol, crystals melting at88.0°-88.5° C. were obtained. The properties of the objective compound(I c-2) are shown in Table 13.

                                      TABLE 13                                    __________________________________________________________________________         m.p. (°C.)                                                        Compd.                                                                             (Recrystalli-                                                                        Elementary Analysis                                               No.  zing solvent)                                                                        Found (Calcd.) (%)                                                                        IR (cm.sup.-1)                                                                        NMR δ                                   __________________________________________________________________________    Ic-1 maleate                                                                              C.sub.19 H.sub.25 N.sub.3 O.sub.2.                                                        (Nujol) (CD.sub.3 OD)                                      145.0-148.0                                                                          C.sub.4 H.sub.4 O.sub.4                                                                   maleate maleate                                            (i-PrOH-                                                                             C, 62.35 (62.29)                                                                          3300, 2910, 2840                                                                      1.95-2.15 (m, 4H), 2.61 (t, J=8Hz, 2H),            Et.sub.2 O)                                                                          H,  6.62  (6.59)                                                                          1705, 1675, 1620                                                                      2.90 (br., 2H), 3.25-3.35 (m, 2H), 3.43                   N,  9.46  (9.48)                                                                          1580, 1510                                                                            (t, J=6Hz, 2H), 3.58 (br., 2H), 3.81 (t,                                      t=7Hz, 2H), 3.96 (br., 2H), 6.15 (br.,                                        1H),                                                                          6.25 (s, 2H), 7.30-7.55(m, 5H)                Ic-2 88.0-88.5                                                                            C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl                                                      (CHCl.sub.3)                                                                          (CDCl.sub.3)                                       (i-PrOH-                                                                             C, 63.16 (63.06)                                                                          3275, 2850, 1705                                                                      1.75-1.90 (m, 2H), 2.02 (quint, J=7Hz,                                        2H),                                               Et.sub.2 O)                                                                          H,  6.74  (6.68)                                                                          1530    2.47-2.75 (m, 8H), 3.16 (q, J= 3Hz, 2H),                  N, 11.61 (11.61)    3.38 (q, J=6Hz, 2H), 3.86 (t, J=7Hz,                                          2H),                                                      Cl, 10.02 (9.80)    6.05 (br., 1H), 7.27, 7.30 (A.sub.2                                           B.sub.2, J=7Hz, 4H)                                                           8.48 (br., 1H)                                __________________________________________________________________________

EXAMPLE 681-[[2-[4-(4-Chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-carbamoyl]-2-oxopyrrolidine(I a-29) ##STR83##

A solution of 1.68 g (4.59 mmol) of1-[[2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine(I a-25) and 1.05 g (5.5 mmol) of p-toluenesulfonic acid monohydrate in75 ml of toluene was refluxed for 25 hr. using a Dean-Stark trapcontaining 10 g of Molecular Sieves-4A. By proceeding as in Example 67,1.57 g of the objective compound (I a-29) was obtained.

Yield: 98.3%.

EXAMPLE 69-72

In the same method as in Example 68, the reactions were carried outunder the conditions shown in Tables 14 and 15, whereby the objectivecompounds (I c) were obtained. The properties are shown in Table 16.

                                      TABLE 14                                    __________________________________________________________________________     ##STR84##                                                                                                         Compound (Ic)                                   Compd. (Ia)                                                                             p-TsOH.H.sub.2 O                                                                     Toluene                                                                              Refluxing                                                                           Yield                                    Ex. No.                                                                              n g (mmol)                                                                              g (mmol)                                                                             (ml)   Time (hr.)                                                                          (g)   (%)                                                                              No.                             __________________________________________________________________________    69     3 4.23    2.75   250    26    3.94  98.2                                                                             Ic-3                                     (12.0)  (14.4)                                                       70     2 2.00    1.46   150    25    1.75  92.4                                                                             Ic-4                                     (5.93)  (7.70)                                                       __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________     ##STR85##                                                                                                             Compound (Ic)                                 Compd. (Ia)                                                                              p-TsOH.H.sub.2 O                                                                     Toluene Refluxing                                                                           Yield                                Ex. No.  n g (mmol) g (mmol)                                                                             (ml)    Time (hr.)                                                                          (g)    (%)                                                                              No.                        __________________________________________________________________________    71       3 4.40     2.97   250     48    3.57   85.0                                                                             Ic-5                                  (11.6)   (15.6)                                                    72       2 1.60     1.12   120     48    1.52   92.1                                                                             Ic-6                                  (4.37)   (5.90)                                                    __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________         m.p. (°C.)                                                        Compd.                                                                             (Recrystalli-                                                                        Elementary Analysis                                                                       IR (cm.sup.-1)                                        No.  zing solvent)                                                                        Found (Calcd.) (%)                                                                        (CHCl.sub.3)                                                                          NMR (CDCl.sub.3) δ                      __________________________________________________________________________    Ic-3 maleate                                                                              C.sub.17 H.sub.23 N.sub.3 O.sub.2 S.                                                      (Nujol) (free base)                                        152.0-153.5                                                                          C.sub.4 H.sub.4 O.sub.4                                                                   maleate 1.804 (quint, J=7Hz, 2H), 2.015 (quint,            (MeOH- C, 56.06 (56.11)                                                                          3320, 1715, 1690                                                                      J=7Hz, 2H) 2.50-2.75 (m, 8H), 3.131                                           (quint,                                            i-PrOH)                                                                              H,  5.95  (6.05)                                                                          1620, 1595, 1530                                                                      J=3Hz, 2H), 3.380 (q, J=6Hz, 2H), 3.855                   N,  9.41  (9.35)    (t, J=7Hz, 2H), 6.075 (m, 1H), 6.90-7.30                  S,  7.04  (7.13)    (m, 3H), 8.499 (br., 1H)                      Ic-4 98.5-100                                                                             C.sub.16 H.sub.21 N.sub.3 O.sub.2 S                                                       3300, 1730, 1675                                                                      2.022 (quint, J=7.2Hz, 2H), 2.55-2.80                                         (m,                                                (i-PrOH-                                                                             C, 60.26 (60.16)                                                                          1540    8H), 3.194 (q, J=3Hz, 2H), 3.489 (q,                                          J=6Hz,                                             Et.sub.2 O)                                                                          H,  6.62  (6.63)    2H), 3.858 (t, J=7Hz, 2H), 6.071 (m,                                          1H),                                                      N, 13.09 (13.16)    6.90-7.15 (m, 3H), 8.613 (br., 1H)                        S,  9.88 (10.04)                                                  Ic-5 maleate                                                                              C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl.                                                     (Nujol) (free base)                                        134.5-135.5                                                                          C.sub.4 H.sub.4 O.sub.4 1/5H.sub.2 O                                                      maleate 1.845 (quint, J=7Hz, 2H), 2.014 (quint,            (i-PrOH)                                                                             C, 57.46 (57.37)                                                                          3290, 1695, 1610                                                                      J=7Hz, 2H), 2.30-2.40 (m, 2H), 2.55-2.65                  H,  5.82  (5.94)                                                                          1570 (sh), 1525                                                                       m, 6H), 3.27-3.30 (m, 2H), 3.392 (q,                                          J=6Hz,                                                    N,  8.56  (8.73)                                                                          1450    2H), 3.854 (t, J=7Hz, 2H), 6.09-6.12 (m,                  Cl, 7.29  (7.36)    1H), 7.264 (s, 4H), 8.499 (br. s, 1H)         Ic-6 102.5-104.0                                                                          C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl                                                      3290, 1705, 1670                                                                      2.026 (quint, J=7Hz, 2H), 2.343-2.380              (MeOH- C, 62.10 (62.15)                                                                          1540, 1520 (sh),                                                                      (m, 2H), 2.558-2.757 (m, 6H), 3.357 (s,                                       2H),                                               Et.sub.2 O)                                                                          H,  6.35  (6.37)                                                                          1485    3.527 (q, J=5.6Hz, 2H), 3.864 (t, J=7Hz,                  N, 11.91 (12.08)    2H), 6.10-6.15 (m, 1H), 7.265 (s, 4H),                    Cl, 9.99  (10.19)   8.624 (br. s, 1H)                             __________________________________________________________________________

REFERENTIAL EXAMPLE 1 2-Oxo-1-phenoxycarbonylpyrrolidine ##STR86##

To a solution of 7.36 g (184 mmol) of NaH (60%) in 200 ml of THF wasadded 15.68 g (184 mmol) of 2-oxopyrrolidine with stirring underice-cooling, and further the mixture was stirred at room temperature for1 hr. until H₂ gas ceased to evolve. The reaction solution was added toa solution of 29.7 g (190 mmol) of phenyl chloroformate in 100 ml of THFcooled at -60° C. and then stirred at room temperature for 4 hr. Thereaction solution was poured into ice water, and then extracted withethyl acetate. After drying, the solvent was removed by evaporation.When the crystalline residue was recrystallized from CH₂ Cl₂ -ether,37.8 g of the objective compound (II) melting at 120.0°-121.5° C. wasobtained as crystals. Yield: 84.0%.

The properties of the objective compound are shown in Table 17.

REFERENTIAL EXAMPLE 2 1-(2-Chloroethylcarbamoyl)-2-oxopyrrolidine(III-1) ##STR87##

A mixture of 65.1 g (765 mmol) of 2-oxopyrrolidine and 67.3 g (638 mmol)of chloroethyl isocyanate was heated with stirring at 95°-105° C.overnight. After cooling, the reaction solution was refined by silicagel chromatography. The resulting compound obtained from the eluate withtoluene-ethyl acetate (20/1-10/1 v/v) was recrystallized from CH₂ Cl₂-ether-n-hexane, whereby 107.7 g of the objective compound1-(2-chloroethylcarbamoyl)-2-oxopyrrolidine (III-1) melting at66.5°-67.5° C. was obtained as crystals.

Yield: 88.5%.

The properties of the objective compound are shown in Table 17.

REFERENTIAL EXAMPLE 3 1-(3-Chloropropylcarbamoyl)-2-oxopyrrolidine(III-2) ##STR88##

A mixture of 17.1 g (201 mmol) of 2-oxopyrrolidine and 20 g (167 mmol)of chloropropyl isocyanate was heated with stirring at 95°-105° C.overnight. After cooling, the reaction solution was refined by silicagel chromatography. The resulting product obtained from the eluate withtoluene-ethyl acetate (20/1-10/1 v/v) was washed with ether-n-hexane andthen collected by filtration, whereby 27.87 g of the objective compound1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine (III-2) melting at57.0°-58.0° C. was obtained as crystals. Yield: 81.0%.

The properties of the objective compound are shown in Table 17.

                                      TABLE 17                                    __________________________________________________________________________    Ref. m.p. (°C.)                                                        Ex.  (Recrystalli-                                                                        Elementary Analysis                                                                       IR (cm.sup.-1)                                        No.  zing solvent)                                                                        Found (Calcd.) (%)                                                                        (CHCl.sub.3)                                                                          NMR (CDCl.sub.3) δ                      __________________________________________________________________________    1    120.0-121.5                                                                          C.sub.11 H.sub.11 NO.sub.3                                                                1795, 1750 (sh),                                                                      2.09 (quint, J=7Hz, 2H), 2.60 (t, J=7Hz,                                      2H)                                                (CH.sub.2 Cl.sub.2 -                                                                 C, 64.43 (64.38)                                                                          1730, 1590, 1485                                                                      3.93 (t, J=7Hz, 2H), 7.10-7.50 (m, 5H)             Et.sub.2 O)                                                                          H,  5.33  (5.40)                                                              N,  6.87  (6.83)                                                  2    66.5-67.5                                                                            C.sub.7 H.sub.11 N.sub.2 O.sub.2 Cl                                                       3300, 1705, 1680                                                                      2.04 (quint, J=7Hz, 2H), 2.63 (t, J=7Hz,                                      2H)                                                (CH.sub.2 Cl.sub.2 -                                                                 C, 43.83 (44.10)                                                                          1540    3.63 (s, 2H), 3.66 (s, 2H), 3.87 (t,                                          J=7Hz,                                             Et.sub.2 O-                                                                          H,  5.80  (5.82)    2H), 8.77 (br. s, 1H)                              n-hexane)                                                                            N, 14.88 (14.70)                                                              Cl, 18.80 (18.60)                                                 3    57.0-58.0                                                                            C.sub.8 H.sub.13 N.sub.2 O.sub.2 Cl                                                       3275, 1700,                                                                           1.80-2.20 (m, 4H), 2.60 (t, J=7Hz, 2H),                                       3.45                                               (Et.sub.2 O-                                                                         C, 46.96 (46.95)                                                                          1670 (sh), 1530,                                                                      (q, J=6Hz, 2H), 3.84 (t, J=6Hz, 2H),                                          8.46                                               n-hexane)                                                                            H,  6.37  (6.40)    (br. s, 1H)                                               N, 13.78 (13.69)                                                              Cl, 17.48 (17.32)                                                 __________________________________________________________________________

Preparation

    ______________________________________                                        1-[[2-(4-Methoxyphenyl)aminoethyl]-                                                                  10 mg                                                  carbamoyl]-2-oxopyrrolidine                                                   Wheat starch           48 mg                                                  Magnesium stearate      2 mg                                                  ______________________________________                                    

The above ingregients are admixed each other to prepare a capsule.

Effect of the Invention

Carbamoylpyrrolidone derivatives (I) of the present invention showedgood activity against amnesia introduced by electro convulsive shock.

In the following experiment of the compounds of this invention, thenumberes of the test compounds correspond to them in Examples and/orTables.

Experiment Prevention against the ECS-Induced Amnesia in Mice

The test apparatus was a black acrylic resin box (30×30×30 cm) with anelectrifiable grid floor in which a white wooden platform (10×10×1 cm)was placed in one corner. The step-down passive avoidance test wasconducted on 3 groups of 10 SD mice each (male, 4 to 5 weeks age). Asolvent was orally administered to the animals of the first group as acontrol group and the test compounds at doses of 5 and 50 mg/kg wereorally given to other 2 groups 60 min. before the acquisition trial. Inthe acquisition trail, mice were individually placed on the platform anda scrambled foot shock (3 mA, for 5 sec.) was delivered through the gridfloor as soon as the mouse moved off the platform. Five to ten min.after the foot shock, a single electroconvulsive shock (30 mA, 100 Hz(rectangular wave), for 0.2 sec.) was administered transcorneally andthen each animal was placed in the home cage. After 24 hr. later, eachmouse was again placed on the platform and the latency for descending onthe grid floor was measured. A long latency in the retention testindicates good acquisition. The step-down latencies were evaluated usingthe Mann-Whitney U-test.

In Table 5, the results were shown as percent change in latencies overcontrol defined as 100.

                  TABLE 5                                                         ______________________________________                                        Effects of Compounds against Amnesia Induced by Electro                       Convulsive Shock                                                              Compound No.    5 mg/kg     50 mg/kg                                          ______________________________________                                        Ia-1            302***      219*                                              Ia-5            166**       108                                               Ia-18           223*        249**                                             Ia-25           222***      205***                                            Ia-45           144         181***                                            Ia-53           181**       122                                               ______________________________________                                         *p < 0.05                                                                     **p < 0.025                                                                   ***p < 0.01                                                              

What we claim is:
 1. A compound of the formula: ##STR89## wherein R is##STR90## wherein one of A and B is ##STR91## and the other is >CH₂ ; R¹is hydrogen or C₁ -C₅ alkyl; Z⁵ is thienyl or phenyl each optionallysubstituted by a halogen, methoxy, or methyl group; Z⁶ is thienyl orphenyl each optionally substituted by a halogen, methoxy, or methylgroup; n is an integer from 2 to 3; and the pharmaceutically acceptableacid addition salts thereof.
 2. A compound as claimed in claim 1, whichis1-[[2-[4-(4-chlorophenyl)-1,2,3,6--tetrahydropyridin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine.3. A compound as claimed in claim 1, which is1-[[3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]propyl]carbamoyl]-2-oxopyrrolidine.4. A compound as claimed in claim 1, which is1-[2-(4-chlorophenyl-4-hydroxypiperidino)ethylcarbamoyl]-2-oxopyrrolidine.5. A compound as claimed in claim 1, which is1-[3-(4-chlorophenyl-4-hydroxypiperidino)propylcarbamoyl]-2-oxopyrrolidine6. A pharmaceutical composition for treating a patient suffering fromsenile dementia comprising a pharmacologically effective amount of acompound claimed in claim 1, together with a carrier, diluent, and/orexcipient therefor.